Methanol extract of Ficus platyphylla ameliorates seizure severity,cognitive deficit and neuronal cell loss in pentylenetetrazole-kindled mice

Decoctions of Ficus plathyphylla are used in Nigeria's folk medicine to manage epilepsy for many years and their efficacies are widely acclaimed among the rural communities of Northern Nigeria. In this study, we examined the ameliorative effects of the standardized methanol extract of Ficus platyphylla (FP) stem bark on seizure severity, cognitive deficit and neuronal cell loss in pentylenetetrazole-kindled mice. The ³⁵S-GTPγS, glutamate and γ-aminobutyric acid receptors binding properties of the extract were also evaluated. Male CD-1 mice were kindled with an initial subeffective dose of pentylenetetrazole (PTZ, 37.5 mg/kg, i.p.) for a total of 13 convulsant injections and the treatment groups concurrently received FP (100 and 200 mg/kg). Control animals received the same number of saline injections. Twenty-four h after kindling completion the animals’ learning performance was tested in a two-way shuttle-box. The animals were challenged with another subeffective dose of PTZ (32.5 mg/kg, i.p.) on day 7 after kindling completion. Animals were sacrificed a day after the challenged experiment and the brains were processed for histological investigation. FP ameliorates seizure severity, cognitive deficits and neuronal cell loss in PTZ kindled mice. Components of the extract showed affinity for GABAergic and glutamatergic receptors. Glutamate release was diminished and the ³⁵S-GTPγS binding assay revealed no intrinsic activity at glutamatergic receptors. Our results revealed that FP contains psychoactive secondary metabolites with anticonvulsant properties, thus supporting the isolation and development of the biologically active components of this medicinal plant as antiepileptic agents.     

Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP)

Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED₅₀ 164 mg/kg), mouse MES (ED₅₀ 83.5 mg/kg) and rat MES (ED₅₀ 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED₅₀ 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.     

Role of Glutamate and GABA Transporters in Development of Pentylenetetrazol-Kindling

Kindling is a form of epileptogenesis that can be induced with pentylenetetrazol (PTZ). We undertook this study to evaluate the contribution of glutamate and GABA transporters to the process of PTZ kindling. Rats were injected i.p. three times per week with PTZ (40 mg/kg) until they were fully kindled. In rats who achieved full kindling, measurement of hippocampal glutamate and GABA transporters within 24 h by western blot showed that GLAST, GLT-1, and EAAC1 were elevated significantly. However, fully kindled rats at 30 days after their last seizure had no change in either glutamate or GABA transporters proteins. These sequential observations suggest that glutamate transporters may contribute to the occurrence of seizures, but were not associated with maintenance of epileptogenesis. During this experiment, we collected data from animals that had kindled easily and animals who were resistant to kindling. Easily-kindled rats reached full kindling with less than five injections of PTZ. Kindling resistant animals failed to achieve full kindling even after administration of 12 consecutive injections of PTZ. Levels of EAAC1 and GAT-1 in easily-kindled rats were decreased by 30% when compared to kindling resistant animals at 30 days after the last PTZ injection. Since decreased EAAC1 and GAT-1 would diminish GABA function, less quantity of these proteins would appear to be associated with the convulsive threshold at the beginning of kindling development. We wonder if glutamate and GABA transporters might be operant in a convulsion threshold set factor or as a pace factor for kindling.     

The contribution of serotonin 5-HT2C and melanocortin-4 receptors to the satiety signaling of glucagon-like peptide 1 and liraglutide, a glucagon-like peptide 1 receptor agonist, in mice

Glucagon-like peptide 1 (GLP-1), an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L-cells, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, induce satiety. The serotonin 5-HT2C receptor (5-HT2CR) and melanoroctin-4 receptor (MC4R) are involved in the regulation of food intake. Here we show that systemic administration of GLP-1 (50 and 200μg/kg)-induced anorexia was blunted in mice with a 5HT2CR null mutation, and was attenuated in mice with a heterozygous MC4R mutation. On the other hand, systemic administration of liraglutide (50 and 100μg/kg) suppressed food intake in mice lacking 5-HT2CR, mice with a heterozygous mutation of MC4R and wild-type mice matched for age. Moreover, once-daily consecutive intraperitoneal administration of liraglutide (100μg/kg) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of MC4R as well as wild-type mice. These findings suggest that GLP-1 and liraglutide induce anorexia via different central pathways.     

The contribution of serotonin 5-HT2C and melanocortin-4 receptors to the satiety signaling of glucagon-like peptide 1 and liragultide, a glucagon-like peptide 1 receptor agonist, in mice

Glucagon-like peptide 1 (GLP-1), an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L-cells, and liraglutide, a GLP-1 receptor (GLP-1R) agonist, induce satiety. The serotonin 5-HT2C receptor (5-HT2CR) and melanoroctin-4 receptor (MC4R) are involved in the regulation of food intake. Here we show that systemic administration of GLP-1 (50 and 200 μg/kg)-induced anorexia was blunted in mice with a 5HT2CR null mutation, and was attenuated in mice with a heterozygous MC4R mutation. On the other hand, systemic administration of liraglutide (50 and 100 μg/kg) suppressed food intake in mice lacking 5-HT2CR, mice with a heterozygous mutation of MC4R and wild-type mice matched for age. Moreover, once-daily consecutive intraperitoneal administration of liraglutide (100 μg/kg) over 3 days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of MC4R as well as wild-type mice. These findings suggest that GLP-1 and liraglutide induce anorexia via different central pathways.     

Vagus nerve stimulation inhibits seizure activity and protects blood–brain barrier integrity in kindled rats with cortical dysplasia

AimsThis study investigates the effects of vagus nerve stimulation (VNS) on seizure severity and blood–brain barrier (BBB) integrity in kindled rats with cortical dysplasia (CD).Main methodsPregnant rats were exposed to 145 cGy of gamma-irradiation on day 17 of pregnancy. In offsprings, kindling was induced by giving subconvulsive doses of pentylenetetrazole. Left VNS was performed for 48 h at output currents of 0.5 or 1 mA. Horseradish peroxidase (HRP) was used to study the BBB permeability. Immunohistochemistry for occludin and P-glycoprotein (P-gp) was also performed.Key findingsKindled rats with CD exhibited seizures with mean Racine's scores of 3.57 ± 1.2 during video EEG recording. Kindled animals with CD receiving VNS at 0.5 and 1.0 mA did not exhibit either clinical or electrophysiological signs of seizure. Immunostaining for occludin, a tight junction protein, in hippocampus remained relatively intact in all groups. VNS-treated and -untreated kindled animals with CD revealed intense immunostaining for P-gp in hippocampal formation (P < 0.01). Electron microscopic observations revealed frequent transport vesicles containing electron-dense HRP reaction products in the cytoplasm of brain capillary endothelial cells in both cerebral cortex and hippocampus of kindled animals with CD. Those which were exposed to 1 mA VNS were observed to have brain capillary endothelial cells largely devoid of HRP reaction products in both cerebral cortex and hippocampus.SignificanceThe results of this study suggest that VNS therapy at 1 mA inhibits seizure activity and protects BBB integrity by limiting the enhancement of transcellular pathway in kindled animals with CD.     

Transmitter amino acid levels in rat brain regions after amygdala-kindling or chronic electrode implantation without kindling: Evidence for a pro-kindling effect of prolonged electrode implantation

Kindling is a chronic model of epilepsy characterized by a progressive increase in response to the same regularly applied stimulus. The biological basis of the kindling phenomenon requires to be determined, but several studies indicate that alterations in amino acidergic neurotransmission may be involved. In the present experiments, levels of glutamate, aspartate, GABA, glycine, and taurine were determined in 12 brain regions by HPLC in 3 groups of animals: (a) a group which was kindled via electrical stimulation of intraamygdala electrodes and was sacrificed 36 days after the last fully kindled seizure for neurochemical determinations; (b) a group of implanted but nonstimulated rats (surgical control group) in which neurochemical measurements were done at the same time after electrode implantation as the kindled group, and (c) a group of non-implanted, naive control rats. Compared to surgical controls, kindling induced a significant reduction of glutamate, GABA, and taurine in the brain stem (pons/medulla), whereas no differences between both groups were found in any of the other regions. However, both electrode-implanted groups differed significantly from non-implanted naive rats in several regions, indicating that electrode-implantation per se induced long-lasting alterations in transmitter amino acids. The most striking difference to naive controls was an increase of glycine levels in several regions in which this amino acid is known to potentiate glutamatergic transmission. In order to examine the functional consequences of prolonged electrode implantation, seizure thresholds were determined in groups of rats with short and prolonged electrode implantation. Data from these experiments indicated that prolonged electrode implantation per se induces pro-kindling effects, i.e. a dramatic decrease of seizure threshold. The data of this study thus demonstrate that the choice of adequate controls is critical in neurochemical and functional studies on the kindling phenomenon.     

Pharmacological inhibition of inducible nitric oxide synthase attenuates the development of seizures in mice

The present study has been designed to pharmacologically expound the significance of inducible nitric oxide synthase in the pathophysiological progression of seizures using mouse models of chemically induced kindled epilepsy and status epilepticus induced spontaneous recurrent seizures. Pentylenetetrazole (40 mg kg⁻¹) (PTZ) administration every second day for a period of 15 days was used to elicit kindled seizure activity in mice. Severity of kindled seizures was assessed in terms of a composite kindled seizure severity score (KSSS). Pilocarpine (100 mg kg⁻¹) was injected every 20 min until the onset of status epilepticus. A spontaneous recurrent seizure severity score (SRSSS) was recorded as a measure of quantitative assessment of the progressive development of spontaneous recurrent seizures induced after pilocarpine status epilepticus. Sub-acute PTZ administration induced the development of severe form of kindled seizures in mice. Further, pharmacological status epilepticus elicited a progressive evolution of spontaneous recurrent seizures in the animals. However, treatment of aminoguanidine, a relatively selective inhibitor of inducible nitric oxide synthase, markedly and dose dependently suppressed the development of both PTZ induced kindled seizures as well as pilocarpine induced spontaneous recurrent seizures. Therefore inducible nitric oxide synthase may be implicated in the development of seizures.     

Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model

Temporal lobe epilepsy (TLE) is the most common form of drug resistant epilepsy. Current treatment is symptomatic, suppressing seizures, but has no disease modifying effect on epileptogenesis. We examined the effects of Z944, a potent T-type calcium channel antagonist, as an anti-seizure agent and against the progression of kindling in the amygdala kindling model of TLE. The anti-seizure efficacy of Z944 (5mg/kg, 10mg/kg, 30mg/kg and 100mg/kg) was assessed in fully kindled rats (5 class V seizures) as compared to vehicle, ethosuximide (ETX, 100mg/kg) and carbamazepine (30mg/kg). Each animal received the seven treatments in a randomised manner. Seizure class and duration elicited by six post-drug stimulations was determined. To investigate for effects in delaying the progression of kindling, naive animals received Z944 (30mg/kg), ETX (100mg/kg) or vehicle 30-minutes prior to each kindling stimulation up to a maximum of 30 stimulations, with seizure class and duration recorded after each stimulation. At the completion of drug treatment, Ca_V3.1, Ca_V3.2 and Ca_V3.3 mRNA expression levels were assessed in the hippocampus and amygdala using qPCR. Z944 was not effective at suppressing seizures in fully kindled rats compared to vehicle. Animals receiving Z944 required significantly more stimulations to evoke a class III (p<0.05), IV (p<0.01) or V (p<0.0001) seizure, and to reach a fully kindled state (p<0.01), than animals receiving vehicle. There was no significant difference in the mRNA expression of the T-type Ca²⁺ channels in the hippocampus or amygdala. Our results show that selectively targeting T-type Ca²⁺ channels with Z944 inhibits the progression of amygdala kindling. This could be a potential for a new therapeutic intervention to mitigate the development and progression of epilepsy.     

Effect of chronic para-chlorophenylalanine treatment on convulsive-seizure reactions

The effect of chronic para-chlorphenylalanine (PCPA) treatment was investigated in two different seizure models: the pentylenetetrazole (PTX) seizure model in rats and the kindled seizures from rabbit amygdala. Chronic PCPA treatment (21 days) in male albino rats caused a progressive decrease in the 5-hydroxytryptamine (5-HT) brain level between the 1st and the 7th day of PCPA administration. Then the 5-HT level remained low until the end of the experiment. On the background of the low 5-HT level there occurred changes in PTZ convulsive reactions: after the 3rd day of PCPA treatment the convulsive-seizure reactivity was significantly increased and after the 7th, 14th and 21st day the increased seizure reactivity performed only as a tendency, though the 5-HT level was still low. Chronic PCPA treatment (16 days) of rabbits delayed the development of the behavioural kindled seizures. This treatment also reduced the duration of bioelectrical seizures until the 8th day of treatment, especially in the motor cortex. The observed different effect of the chronic PCPA treatment in both seizure models: pentylenetetrazole in rats and kindling in rabbits might be explained by essential differences in the origin and mechanisms of development of the two seizure models.     

Time- and Region-Specific Variations in Somatostatin Release Following Amygdala Kindling in the Rat

Abstract: Somatostatin biosynthesis is activated during and following kindling epileptogenesis. The aim of this study was to investigate whether this phenomenon translates into enhanced release of the peptide and whether it is involved in kindling maintenance. A marked increase in somatostatin-like immunoreactivity (somatostatin-LI) was observed in hilar interneurons of the hippocampus and in their presumed projections to the outer molecular layer 1 week, but not 1 month, after the last kindled seizure. No overt changes were observed in the striatum or in the cortex. Compared with sham-stimulated controls, (a) in the hippocampus, high-K⁺-evoked somatostatin-LI release was unchanged in synaptosomes taken from rats killed 7 days after the last kindled seizure but was bilaterally reduced after 30 days; (b) in the striatum, it was increased (mainly ipsilaterally to stimulation) 7, but not 30, days after the last seizure; and (c) in the cortex, somatostatin-LI release was bilaterally increased in synaptosomes taken from kindled rats 30, but not 7, days after the last seizure. This study shows that distinct changes occur in synaptosomal somatostatin-LI release after kindling acquisition, depending on the brain area analyzed and on the time elapsed from the last generalized seizure.     

Amygdala Kindling Modifies Extracellular Opioid Peptide Content in Rat Hippocampus Measured by Microdialysis

Abstract: Opioid peptide release in the hippocampus was shown to be increased immediately following amygdala kindling stimulation in freely moving rats using microdialysis combined with a universal opioid peptide radioimmunoassay (RIA). Extracellular opioid peptide levels were elevated (55% above basal levels) within the first 10 min after electrical stimulation-induced partial seizures in previously nonkindled animals. Fully kindled rats showed lower extracellular opioid peptide levels (40% reduction) during the interictal period [16 ± 2.1 days (mean ± SEM) after the last stage V seizure], in comparison with values obtained from the sham-kindled group under basal conditions. However, opioid peptide release in fully kindled rats increased above 152% of interictal levels within the first 20 min after onset of fully kindled seizures, attaining peak levels equal to that of the partial kindled group and returning to prestimulation conditions 40–60 min following the ictal events. The majority of the immunoreactive material recovered from the hippocampus within the first 20 min following partial and generalized kindled seizures coeluted with dynorphin-A (1–6), dynorphin-A (1–8), and Leu-enkephalin by HPLC/RIA analysis. It is proposed that the enhanced opioid peptide release in hippocampus induced by amygdala kindling stimulation might be associated with either enhanced excitability or seizure suppression as seizure susceptibility fluctuates. The reduced interictal opioid peptide levels may also underlie some interictal behavioral disturbances.     

Protective Effect of Nerolidol Against Pentylenetetrazol-Induced Kindling,Oxidative Stress and Associated Behavioral Comorbidities in Mice

The present study was aimed to investigate the effect of nerolidol on the development of kindling and associate oxidative stress and behavioral comorbidities. Kindling was induced by repeated injections of a sub-convulsive dose of pentylenetetrazol (PTZ-35 mg/kg; i.p.), at an interval of 48?±?2 h for 43 days (21 injections). Nerolidol was administered daily in three doses (12.5, 25 and 50 mg/kg) along with alternate day PTZ injection. To access behavioral comorbidities, animals were subjected to tail suspension test (TST) and passive shock avoidance (PSA) test to evaluate the associated depression and memory impairment respectively on the last day of PTZ administration. Following behavioral assessment, neurotransmitter level and oxidative stress markers were evaluated in brain. The results showed that nerolidol significantly suppressed the progression of kindling. Also, nerolidol ameliorates the kindling associated depression and memory impairment as indicated by decreased immobility time and increased step down latency, respectively, as compared to vehicle control animals. Further, these behavioral observations were complimented with corresponding neurochemical and oxidative stress markers changes. In conclusion, the results of present study showed that nerolidol treatment has protective effect against PTZ-induced kindling and associated oxidative stress and behavioral comorbidities.     

Psychoneurochemical Investigations to Reveal Neurobiology of Memory Deficit in Epilepsy

Pentylenetetrazole-kindling induced memory deficit has been validated in our previous study. The present study attempts a neurochemical investigation to reveal possible targets for treatment of memory deficit associated with pentylenetetrazole-kindling. Kindling was induced by administering subconvulsive dose of pentylenetetrazole (35 mg/kg; i.p.) at an interval of 48 ± 2 h. Successfully kindled animals were divided into two groups (interictal and postictal group), while non-kindled (naive) animals served as naïve group. In postictal group, animals were challenged with pentylenetetrazole (35 mg/kg) on days 5, 10, 15 and 20. Learning and memory were evaluated in all experimental groups using elevated plus maze and passive shock avoidance paradigm on days 5, 10, 15 and 20. After behavioral evaluations on day 20, all animals were sacrificed to remove their brains. Neurochemical (glutamate, GABA, norepinephrine, dopamine and serotonin) changes and acetylcholinesterase activity and total nitrite level were estimated using HPLC-FD methods and microplate reader method respectively, in discrete brain parts. The results of the neurochemical estimation demonstrated the imbalance in excitatory/inhibitory tone, reduction in monoamine level, elevated nitrosative and acetylcholinesterase activity in the cortex and hippocampus, as responsible factors for the pathobiology of learning and memory deficit in epilepsy. Restoration of these changes may be targeted for the management of memory deficit in epileptic patients.     

Modulation of leukotriene D4 attenuates the development of seizures in mice

The present study has been designed to pharmacologically investigate the effect of Montelukast sodium, a leukotriene D₄ receptor antagonist, and 1,2,3,4, tetrahydroisoquinoline, a leukotriene D₄ synthetic pathway inhibitor, on the pathophysiological progression of seizures using mouse models of kindled epilepsy and status epilepticus induced spontaneous recurrent seizures. Pentylenetetrazole (40 mg kg⁻¹) (PTZ) administration every second day for a period of 15 d was used to elicit chemically induced kindled seizure activity in mice. In a separate set of groups, fifty consecutive electroshocks were delivered to mice using corneal electrodes with continuously increasing intensity with an inter-shock interval of 40 s. Severity of kindled seizures was assessed in terms of a composite kindled seizure severity score (KSSS). Pilocarpine (100 mg kg⁻¹) was injected every twenty minutes until the onset of status epilepticus. A spontaneous recurrent seizure severity score (SRSSS) was recorded as a measure of quantitative assessment of the progressive development of spontaneous recurrent seizures induced after pilocarpine status epilepticus. Sub-acute PTZ administration and electroshock induced the development of severe form of kindled seizures in mice. Severity of kindled seizures was assessed in terms of a composite kindled seizure severity score. Further, pharmacological status epilepticus elicited a progressive evolution of spontaneous recurrent seizures in the animals. However, Montelukast sodium, a leukotriene D₄ receptor antagonist, as well as 1,2,3,4, tetrahydroisoquinoline, a leukotriene D₄ synthetic pathway inhibitor, markedly and dose dependently suppressed the development of kindled seizures as well as pilocarpine induced spontaneous recurrent seizures. Therefore, leukotriene D₄ may be implicated in the pathogenesis of seizures.     

The Role of the Possible Receptors and Intracellular Pathways in Protective Effect of Exogenous Anandamide in Kindling Model of Epilepsy

In this research, the involvement of CB1 and TRPV1 receptors in the possible protective effects of anandamide were investigated in the kindling model of epilepsy. The basolateral amygdala of the rat brain was chosen to put stimulating electrodes. Semi-rapid kindling was induced by a repetitive sub-threshold stimulation for 5–9 consecutive days. There were seven groups, six of which were kindled and used for drug testing by intracerebroventricular (i.c.v.) microinjection. (i) Sham, (ii) control group received vehicles, (iii) anandamide (AEA; 100 ng/rat), (iv) capsazepine (TRPV1 antagonist; 100 ng/rat), (v) AM251 (CB1 antagonist; 100 ng/rat), (vi) AM251?+?anandamide, and (vii) capsazepine?+?anandamide. The after-discharge duration, seizure duration, and stage five duration were measured in rats. Moreover, the expressions of the extracellular signal-regulated kinase (ERK) and the cAMP responsive element binding (CREB) proteins in the hippocampus were also studied. The anandamide-treated group showed a significant decrease in seizure scores, while no change was shown in seizure scores in the capsazepine- and AM251-treated groups compared with the control group. Co-administrations of either capsazepine?+?AEA or AM251?+?AEA attenuated the protective effect of AEA against seizure. Furthermore, the group received AEA showed a decrease in the expressions of CREB and p-CREB possibly through the activation of the CB1 and TRPV1 receptors. Activation of CB1 and TRPV1 receptors might be involved in AEA anticonvulsant effect in kindling model of epilepsy. This effect could be due to suppression of CREB phosphorylation in hippocampal neurons.

     

Effects of organic calcium antagonists and magnesium on the development of corazol kindling

In experiments on rats it was shown that i.p. administration of finoptin (verapamil), magnesium sulfate or ryodipine (an 1,4-dihydropyridine) 15 min before each daily injection of pentylenetetrazole (PTZ) in a subconvulsive dose (30 mg/kg i.p.) significantly (for 10-12 days delayed the development of pentylenetetrazole-induced kindling and attenuated kindled seizure reaction as compared with the controls. In animals sensitive to PTZ which were selected on the test of their reaction to previous single PTZ injection in a dose of 40 mg/kg finoptin, magnesium or finoptin + magnesium resulted in suppression of kindling development at late stages (after 2-week administration of drugs together with PTZ). After the withdrawal of the drugs there was a tendency to an increase of seizure reaction to the testing PTZ dose (30 mg/kg). The enhanced seizure susceptibility to test PTZ dose has being persisted during all observation period (8 months). Finoptin administered 15 min prior to PTZ had no effect on the severity of seizure reaction of fully kindled animals which had not received the drugs. The results obtained show that organic Ca-antagonists and magnesium delay the development of kindling induced seizure susceptibility, but cannot completely prevent it. The results also suggest that mechanisms of the chronic epileptogenesis (development of kindling induced seizure susceptibility) and those of the acute convulsive reaction to the epileptogen are not similar.     

Sexually dimorphic responses to neonatal basal forebrain lesions in mice: I. Behavior and neurochemistry

The nucleus basalis magnocellularis (nBM) provides the primary source of cholinergic input to the cortex. Neonatal lesions of the nBM produce transient reductions in cholinergic markers, persistent abnormalities in cortical morphology, and spatial navigation impairments in adult mice. The present study examined sex differences in the effects of an electrolytic nBM lesion on postnatal day 1 (PND 1) in mice on behavior and neurochemistry in adulthood. Mice were lesioned on PND 1 and tested at 8 weeks of age on a battery of behavioral tests including passive avoidance, cued and spatial tasks in the Morris water maze, simple and delayed nonmatch to sample versions of an odor discrimination task, and locomotor activity measurements. Following behavioral testing, mice were sacrificed for either morphological assessment or neurochemical analysis of a cholinergic marker or catecholamines. There were no lesion or sex differences in acquisition or retention of passive avoidance, performance of the odor discrimination tasks, or activity levels. Control mice showed a robust sex difference in performance of the spatial water maze task. The lesion produced a slight cued but more dramatic spatial navigation deficit in the water maze which affected only the male mice. Neurochemical analyses revealed no lesion-induced changes in either choline acetyltransferase activity or levels of norepinephrine or serotonin at the time of testing. The subsequent report shows a sex difference in lesion-induced changes in cortical morphology which suggests that sexually dimorphic cholinergic influences on cortical development are responsible for the behavioral deficits seen in this study. © 1998 John Wiley & Sons, Inc. J Neurobiol 37: 582–594, 1998     

Amygdala adenosine A1 receptors have no anticonvulsant effect on piriform cortex-kindled seizures in rat

Adenosine is an endogenous anticonvulsant that exerts its effects through A1 receptors. As the piriform/amygdala is a critical circuit for limbic seizure propagation, in this study, the role of basolateral amygdala A1 receptors on piriform cortex (PC)-kindled seizures was investigated. Rats were kindled by daily electrical stimulation of PC. In fully kindled animals, bilateral intra-amygdala N6-cyclohexyladenosine (CHA; 10-500 micromol/L, a selective A1 receptor agonist) had no effect on kindled-seizure parameters. However, bilateral intra-amygdala 2% lidocaine (reversal neuronal inhibitor) reduced the kindled seizure severity. There was significant increase in stage 4 latency and decrease in stage 5 duration. Bilateral lesion of basolateral amygdala of kindled animals (by electrical DC current) reduced the kindled seizure severity more dramatically. Our results showed afterdischarge duration, stage 5 duration, and seizure duration were decreased and stage 4 latency increased significantly. In addition, daily intra-amygdala CHA had no significant effect on PC kindling acquisition. Therefore, it may be concluded that although the basolateral amygdala neuronal activity has a critical role in the propagation of epileptic seizures from PC, the amygdala A1 receptors have no role in this regard. On the other hand, amygdala A1 receptors have no anticonvulsant or antiepileptogenic effect on PC-kindled seizures.