Long­term effects of vitexin against development of pentylenetetrazole­induced kindling in rats.

Evidence is provided that the glycosylated flavonoid vitexin (apigenin­8­C­beta­D­glucopyranoside) attenuates pentylenetetrazole (PTZ)­induced acute tonic­clonic seizures in rats. However, the effects of chronic and systemic vitexin in PTZ­kindled rats remain unknown. The aim of this work was to investigate the effect of long­term treatment with vitexin in the PTZ­kindling model of epilepsy. Male Wistar rats received intraperitoneal injections of PTZ at a subconvulsive dose of 35 mg/kg every other day for 29 days. Either saline containing dimethyl sulfoxide - DMSO 1%  (vehicle), diazepam (2 mg/kg; positive control) or vitexin (2.5 mg/kg) was administered intraperitoneally 30 min before each PTZ injection. The behavioral reactions were recorded by 30 min immediately after each PTZ injection. Furthermore, on the 31st day, that is, 48 h after the latter dose of PTZ, the animals were euthanized and renal and hepatic biochemical markers were evaluated in blood serum. Chronic treatment with either diazepam or vitexin attenuated the seizures provoked by PTZ injections. Neither diazepam nor vitexin caused changes in renal levels of creatinine and urea and in hepatic levels of aspartate aminotransferase and alanine aminotransferase. Our findings suggest that chronic administration of vitexin attenuates the progression of PTZ­induced kindling without causing side effects on kidneys and liver.

Piroxicam reduced the intensity of epileptic seizures in a kindling seizure model.

Introduction: The close relationship between inflammatory processes and epileptic seizures is already known, although the exact pathophysiological mechanism is unclear. In this study, the anticonvulsant capacity of piroxicam, an anti-inflammatory drug, was evaluated. A rat pentylenetetrazole kindling model was used.Methods: Male Wistar rats, 8-9 weeks old, received piroxicam (0.15 and 0.30 mg/kg), diazepam (2 mg/kg) or saline for 14 days, and PTZ, on alternate days. Intraperitoneal was chosen as the route of administration. The intensity of epileptic seizures was assessed using a modified Racine scale. The open field test and object recognition analysis were performed at the beginning of the study to ensure the safety of the drugs used. At the end of the protocol, the animals were euthanized to measure the levels of inflammatory (TNF-a and IL-6) and anti-inflammatory (IL-10) cytokines in the cortex, hippocampus, and serum.Results:There were no changes in the open field test and object recognition analysis. Piroxicam was found to decrease Racine scale scores at both concentrations. The reported values for IL-6 levels remained steady in all structures, whereas the TNF-alpha level in the cortex was higher in animals treated with piroxicam than in the saline and diazepam subjects. Finally, animals treated with the anti-inflammatory drug presented reduced IL-10 levels in the cortex and hippocampus.onclusions: Using inflammation as a guiding principle, the anticonvulsant effect of PIRO could be associated with the hippocampal circuits, since this structure showed no increase in inflammatory cytokines.

Lacosamide improves biochemical, genotoxic, and mitochondrial parameters after PTZ-kindling model in mice.

This study evaluated the effect of lacosamide (LCM) on biochemical and mitochondrial parameters after PTZ kindling in mice. Male mice were treated on alternative days for a period of 11 days with LCM (20, 30, or 40 mg/kg), saline, or diazepam (2 mg/kg), before PTZ administration (50 mg/kg). The hippocampi were collected to evaluate free radicals, the activities of superoxide dismutase (SOD), catalase (CAT), and the mitochondrial complexes I-III, II, and II-III, as well as Bcl-2 and cyclo-oxygenase-2 (COX-2) expressions. Hippocampi, blood, and bone marrow were collected for genotoxic and mutagenic evaluations. LCM 40 mg/kg increased latency and decreased percentage of seizures, only on the 3rd day of observation. The dose of 30 mg/kg only showed positive effects on the percentage of seizures on the 2nd day of observation. LCM decreased free radicals and SOD activity and the dose of 40 mg/kg were able to increase CAT activity. LCM 30 and 40 mg/kg improved the enzymatic mitochondrial activity of the complex I-III and LCM 30 mg/kg improved the activity of the complex II. In the comet assay, the damage induced by PTZ administration was reduced by LCM 20 and 30 mg/kg. The dose of 20 mg/kg increased COX-2 expression while the highest dose used, 40 mg/kg, was able to reduce this expression when compared to the group treated with LCM 20 mg/kg. Although LCM did not produce the antiepileptogenic effect in vivo, it showed the neuroprotective effect against oxidative stress, bioenergetic dysfunction, and DNA damage induced by the repeated PTZ administration.

Prevention of pentylenetetrazole-induced kindling and behavioral comorbidities in mice by levetiracetam combined with the GLP-1 agonist liraglutide: Involvement of brain antioxidant and BDNF upregulating properties.

Kindling is a model for studying epileptogenesis and associated neuropsychiatric conditions. The antiepileptic drug levetiracetam (LEV) presents anti-kindling properties, but some severe neuropsychiatric events, especially depression, have been associated with its use in epileptic patients. The positive modulation of glucagon-like peptide-1 (GLP-1) receptors emerged as a potential target for the treatment of epilepsy and other neurological disorders. Here, we investigated behavioral and neurochemical effects of liraglutide (LIRA), a GLP-1 receptor agonist, alone or combined with LEV in mice subjected to PTZ-induced kindling. Male mice received PTZ on alternate days for 21 days. Before PTZ, the animals received LIRA, LEV (alone or in combination with LIRA) or saline. After seizures staging according to Racine's scale, behavioral evaluations were performed to verify anxiety-, depressive-like and cognitive performance. Brain oxidative alterations and BDNF levels were also measured. LEV showed anti-kindling properties, but aggravated depressive-like behavior in PTZ-kindling. In control conditions, LEV induced a pro-depressant effect and impaired avoidance memory retention. LIRA delayed but did not prevent the full kindling development. LIRA prevented the depressive-like behavior induced by PTZ kindling and PTZ + LEV. LEV + LIRA protected against PTZ-induced anxiety-like alterations and impairments in locomotion and cognition. Furthermore, LEV + LIRA reduced nitrite levels and lipid peroxidation in the hippocampus and prefrontal cortex, while it increased reduced glutathione levels in all evaluated brain areas. LIRA or LEV + LIRA increased hippocampal BDNF levels. In conclusion, our results showed that LIRA can be a promising adjunctive therapy for epilepsy-related neuropsychiatric comorbidities and to improve the management of antiepileptic drug associated behavioral adverse effects.

Effect of dexamethasone on seizures and inflammatory profile induced by Kindling Seizure Model.

The objective of this study was to evaluate the effect of dexamethasone, on the severity of seizures and levels of pro-inflammatory interleukins in animals with kindling model induced by pentylenetetrazole (20 mg/kg) in alternated days for 15 days of treatment. The animals were divided into five groups: control group given saline, a group treated with diazepam (2 mg/kg) and groups treated with dexamethasone (1, 2 and 4 mg/kg). Open field test was conducted. The treatment with dexamethasone decreased the severity of seizures, also decreased TNF-alpha and Interleukin 1 beta levels in the hippocampus and TNF-alpha level in the serum.

Comparison of behavioral, neuroprotective, and proinflammatory cytokine modulating effects exercised by (+)-cis-EC and (-)-cis-EC stereoisomers in a PTZ-induced kindling test in mice.

Epoxy-carvone (EC) has chiral centers that allow generation of stereoisomers, including (+)-cis-EC and (-)-cis-EC, whose effects in the kindling tests have never been studied. Accordingly, this study aims to comparatively investigate the effect of stereoisomers (+)-cis-epoxy-carvone and (-)-cis-epoxy-carvone on behavioral changes measured in scores, in the levels of cytokines (IL-1ß, IL-6, and TNFα) and neuronal protection in the face of continuous treatment with pentylenetetrazol. Swiss mice were divided into five groups (n = 10), receiving vehicle, (+) - cis-EC, (-) - cis-EC (both at the dose of 30 mg/kg), and diazepam (4 mg/kg). Thirty minutes after the respective treatment was administered to the animals one subconvulsive dose of PTZ (35 mg/kg). Seven subconvulsives treatments were made on alternate days, in which each treatment several parameters were recorded. In the eighth treatment, the animals receiving the highest dose of PTZ (75 mg/kg) and were sacrificed for quantification of cytokines and histopathologic analysis. All drugs were administered by intraperitoneal route. In the kindling test, (+)-cis-EC and (-)-cis-EC reduced the average scores. The stereoisomer (+)-cis-EC decreased levels of proinflammatory cytokines IL-1ß, IL-6, and TNFα, whereas comparatively (-)-cis-EC did not reduce IL-1ß levels. Histopathological analysis of the mice hippocampi undergoing this methodology showed neural protection for treated with (+)-cis-EC. The results suggest that the anticonvulsant effect of (+)-cis-EC possibly takes place due to reduction of proinflammatory cytokines involved in the epileptogenic process, besides neuronal protection, yet further investigation of the mechanisms involved is required.

Manual acupuncture improves parameters associated with oxidative stress and inflammation in PTZ-induced kindling in mice.

The use of acupuncture in the treatment of central nervous system (CNS) disorders is an age-old practice. Although only a few studies have proved its efficacy, evidence has indicated the use of acupuncture to treat different types of seizures. Therefore, the present study aimed to evaluate the effect of manual acupuncture (MAC) using the chemical kindling model. The role of MAC in oxidative stress and inflammation after pentylenetetrazole (PTZ)-induced kindling was investigated by measuring reactive oxygen species (ROS) production, superoxide dismutase (SOD), and catalase (CAT) activities, nitrite content, and deoxyribonucleic acid (DNA) damage in cerebral cortex. Mice received PTZ (60mg/kgs.c.) once every three days for 16days, totaling six treatments. MAC was applied at acupoint GV20 daily during the entire experimental protocol. Diazepam (DZP) (2mg/kg) was used as positive control. Also, we evaluated the MAC effect associated with DZP (MAC/DZP) at a low dose (0.15mg/kg). The results demonstrated that MAC or MAC/DZP were not able to reduce significantly seizure occurrence or to increase the latency to the first seizure during treatment. MAC/DZP promoted a difference in the first latency to seizure only on the third day. PTZ-induced kindling caused significant neuronal injury, oxidative stress, increased DNA damage, nitric oxide production, and expression of the pro-inflammatory Tumor Necrosis Factor-α (TNF-α). These effects were reversed by treatment with MAC or MAC/DZP. These results indicated that the stimulation of acupoint GV20 by MAC showed no potential antiepileptogenic effect in the model used, although it greatly promoted neuronal protection, which may result from antioxidant and anti-inflammatory effects observed here.

Montelukast reduces seizures in pentylenetetrazol-kindled mice.

Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1 immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.

N-acetylcysteine attenuates nicotine-induced kindling in female periadolescent rats.

Kindling is a form of behavioral sensitization that is related to the progression of several neuropsychiatric disorders such as bipolar disorder. We recently demonstrated that female periadolescent rats are more vulnerable to nicotine (NIC)-induced kindling than their male counterparts. Furthermore, we evidenced that decreases in brain antioxidative defenses may contribute to this gender difference. Here we aimed to determine the preventive effects of the antioxidant N-acetyl cysteine (NAC) against NIC-kindling in female periadolescent rats. To do this female Wistar rats at postnatal day 30 received repeated injections of NIC 2mg/kg, i.p. every weekday for up to 19 days. NAC90, 180 or 270 mg/kg, i.p. was administered 30 min before NIC. The levels of glutathione (GSH), superoxide dismutase (SOD) activity, lipid peroxidation (LP) and nitrite were determined in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). The development of kindling occurred at a median time of 16.5 days with 87.5% of NIC animals presenting stage 5 seizures in the last day of drug administration. NAC270 prevented the occurrence of kindling. NIC-kindled animals presented decreased levels of GSH and increased LP in the PFC, HC and ST, while SOD activity was decreased in the ST. NAC180 or 270 prevented the alterations in GSH induced by NIC, but only NAC270 prevented the alterations in LP. Nitrite levels increased in the ST of NAC270 pretreated NIC-kindled animals. Taken together we demonstrated that NAC presents anti-kindling effects in female animals partially through the restoration of oxidative alterations.

Montelukast reduces seizures in pentylenetetrazol-kindled mice

Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1 immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.

Antiepileptogenic, antioxidant and genotoxic evaluation of rosmarinic acid and its metabolite caffeic acid in mice.

AIMS: Antioxidant compounds have been extensively investigated as a pharmacological alternatives to prevent epileptogenesis. Rosmarinic acid (RA) and caffeic acid (CA) are compounds with antioxidant properties, and RA has been shown to inhibit GABA transaminase activity (in vitro). Our aim was to evaluate the effect of RA and CA on seizures induced by pentylenotetrazole (PTZ) using the kindling model in mice. MAIN METHODS: Male CF-1 mice were treated once every three days during 16days with RA (1, 2 or 4mg/kg; i.p.), or CA (1, 4 or 8mg/kg; i.p.), or positive controls diazepam (1mg/kg; i.p.) or vigabatrin (600mg/kg; p.o.), 30min before PTZ administration (50mg/kg; s.c.). After the last treatment, animals were sacrificed and the cortex was collected to evaluate free radicals (determined by 2',7'-dichlorofluorescein diacetate probe), superoxide dismutase (SOD) and genotoxic activity (Alkaline Comet Assay). KEY FINDINGS: Rosmarinic acid 2mg/kg increased latency and decreased percentage of seizures, only on the 4th day of observation. The other tested doses of RA and CA did not show any effect. Rosmarinic acid 1mg/kg, CA 4mg/kg and CA 8mg/kg decreased free radicals, but no dose altered the levels of enzyme SOD. In the comet assay, RA 4mg/kg and CA 4mg/kg reduced the DNA damage index. SIGNIFICANCE: Some doses of rosmarinic acid and CA tested showed neuroprotective action against oxidative and DNA damage produced in the kindling epilepsy model, although they did not produce antiepileptogenic effect in vivo.

Effects of pentylenetetrazole kindling on mitogen-activated protein kinases levels in neocortex and hippocampus of mice.

The epileptogenesis process involves cell signaling events associated with neuroplasticity. The mitogen-activated protein kinases (MAPKs) integrate signals originating from a variety of extracellular stimuli and may regulate cell differentiation, survival, cell death and synaptic plasticity. Here we compared the total and phosphorylated MAPKs (ERK1/2, JNK1/2 and p38(MAPK)) levels in the neocortex and hippocampus of adult Swiss male mice quantified by western blotting analysis 48 h after the last injection of pentylenetetrazole (PTZ), according to the kindling protocol (35 mg/kg, i.p., on alternated days, with a total of eight injections). The total levels of the investigated MAPKs and the phospho-p38(MAPK) in the neocortex and hippocampus were not affected by the PTZ injections. The MAPKs phosphorylation levels remain unaltered in PTZ-treated animals without convulsive seizures. The phospho-JNK2 phosphorylation, but not the phospho-JNK1, was increased in the hippocampus of PTZ-treated animals showing 1-3 days with convulsive seizures, whereas no significant changes were observed in those animals with more than 3 days with convulsive seizures. The phospho-ERK1/2 phosphorylation decreased in the neocortex and increased in the hippocampus of animals with 1-4 days with convulsive seizures and became unaltered in mice that showed convulsive seizures for more than 4 days. These findings indicate that resistance to PTZ kindling is associated with unaltered ERK1/2, JNK1/2 and p38(MAPK) phosphorylation levels in the neocortex and hippocampus. Moreover, when the PTZ kindling-induced epileptogenesis manifests behaviorally, the activation of the different MAPKs sub-families shows a variable and non-linear pattern in the neocortex and hippocampus.

Electroencephalographic characterization of pentylenetetrazole kindling in rats and modulation of epileptiform discharges by nitric oxide.

Epileptogenesis is a progressive process which culminates with spontaneous, recurrent and unpredictable epileptic seizures due to enhanced neuronal excitability. Well-characterized animal models of this process are needed to clarify its underlying molecular mechanisms, in which the role of nitric oxide has been a controversial component. We have used kindling with a sub-convulsive dose of pentylenetetrazole to objectively characterize early electroencephalographic changes during epileptogenesis. We used electroencephalographic recordings both during pentylenetetrazole (20 mg/kg) kindling for 20 days and then, 24 days later to quantify the number, duration and spectral power of epileptic discharges. The levels of nitric oxide were modulated locally in the cerebral cortex by pharmacological agents. The number of epileptiform discharges increased during the kindling protocol as well as 24 days later, revealing the induction of a self-sustaining epileptogenic process. Epileptic discharges were characterized by theta frequencies (4-10 Hz) that were associated with absence-like seizures. However, during kindling, the spectral power of the theta band progressively decreased, while the power of higher frequencies, in the beta band, increased. Nitric oxide in the cerebral cortex inhibited the number and amplitude of epileptic discharges. The electroencephalographic characterization of this kindling protocol provides a valuable tool to detect consequences of therapeutic interventions undertaken at initial phases of epileptogenesis, especially those targeted towards stopping this process. Increases of nitric oxide in the cerebral cortex could be a useful intervention to negatively modulate neuronal excitability, epileptic discharges and the progression of epileptogenesis.

[Cytokines and the nervous system: the relationship between seizures and epilepsy]. / Citocinas y sistema nervioso: relacion con crisis convulsivas y epilepsia.

INTRODUCTION. The immune system and the peripheral and central nervous system are in constant communication by means of messengers and signalling molecules released, such as cytokines, neuropeptides, neurohormones and neurotransmitters, among others. Seizures are defined as the transitory appearance of signs and symptoms that trigger an abnormally excessive neuronal activity in the brain. Following seizures the generation of a neuroinflammatory process has been observed to occur, with the consequent release of proinflammatory cytokines and inflammation-mediating molecules, which make the patient more prone to epilepsy. AIM. To offer evidence suggesting and supporting the role of cytokines in the appearance of seizures and in epilepsy, since these molecules have proven to have dual properties. DEVELOPMENT. The central nervous system, by means of the blood-brain barrier, restricts the flow of activated cells and inflammation mediators released from the peripheral system towards the brain parenchyma. Moreover, there is also another series of mechanisms that contributes to the 'selective and modified' immunity of the central nervous system. The purpose of all this series of events is to limit the responses of the immune system at central level, although it has been shown that in the central nervous system they are permanently under the control and regulation of the immune system. CONCLUSIONS. Cytokines in epilepsy play a dual role with pro- and anti-convulsive properties. Seizures do not induce the expression of cytokines only inside the brain, but also peripherally.

TITLE: Citocinas y sistema nervioso: relacion con crisis convulsivas y epilepsia.Introduccion. El sistema inmune y el sistema nervioso periferico y central se encuentran en constante comunicacion a traves de mensajeros y moleculas de señalizacion liberadas, como las citocinas, los neuropeptidos, las neurohormonas y los neurotransmisores, entre otros. Las convulsiones se definen como la aparicion transitoria de signos y sintomas que inducen una actividad neuronal excesiva anormal en el cerebro; despues de una crisis convulsiva, se ha observado la generacion de un proceso neuroinflamatorio, con la consecuente liberacion de citocinas proinflamatorias y de moleculas mediadoras de inflamacion, que predisponen a la epilepsia. Objetivo. Mostrar la evidencia que sugiere y apoya el papel de las citocinas en la aparicion de crisis convulsivas y en la epilepsia, ya que estas moleculas han demostrado propiedades duales. Desarrollo. El sistema nervioso central, a traves de la barrera hematoencefalica, restringe el flujo de celulas activadas y de mediadores de inflamacion liberados desde el sistema periferico hacia el parenquima cerebral; ademas, existe otra serie de mecanismos que contribuyen a la inmunidad 'selectiva y modificada' del sistema nervioso central. Toda esta serie de eventos tiene la finalidad de limitar respuestas del sistema inmune a nivel central, aunque se ha demostrado que en el sistema nervioso central se encuentran de manera permanente bajo el control y la regulacion del sistema inmune. Conclusiones. Las citocinas en la epilepsia muestran un papel dual con propiedades pro y anticonvulsionantes. Las convulsiones no solamente inducen la expresion de citocinas dentro del cerebro, sino tambien perifericamente.

Differences in vulnerability to nicotine-induced kindling between female and male periadolescent rats.

RATIONALE: It has recently been reported that chronic nicotine administration at subconvulsive doses causes seizures, a phenomenon referred to as kindling. Evidence points to the involvement of oxidative stress in pharmacological and electrical kindling, sex is known to influence the brain's response to nicotine. OBJECTIVES: This study investigated the sex differences in vulnerability to nicotine-induced kindling and the involvement of oxidative stress in this phenomenon. METHODS: Male and female periadolescent Wistar rats received repeated injections of a subconvulsive dose of nicotine (hemisulfate salt; 2 mg/kg, i.p.) every weekday for up to 25 days. To better understand the influence of oxidative stress in nicotine kindling, the antioxidant vitamin E (200 and 400 mg/kg, p.o.) was administered prior to nicotine administration. The levels of gluthatione (GSH), superoxide dismutase (SOD) activity, and lipid peroxidation were determined in the hippocampus (HC), prefrontal cortex (PFC), and striatum. RESULTS: Female animals developed kindling more rapidly than male rats. In female rats, kindling was associated with decreases in antioxidant defenses, including GSH levels in the HC and striatum and SOD activity in the PFC and striatum, and increased lipid peroxidation in all brain areas studied. By contrast, male kindled animals presented only with a decrease in the GSH in the HC. Vitamin E prevented the occurrence of kindled seizures by 80 % and 75 % in male and female rats, respectively. CONCLUSION: These novel findings indicate that female periadolescent rats develop nicotine-kindled seizures earlier than their male counterparts. Differences in the oxidative balance may be involved in this mechanism.

Changes on D2-like receptor induced Gi protein activation and hippocampal dopamine release in kindled rats.

The present study aimed to characterize dopamine release in the hippocampus and D2-like receptor-induced Gi protein activation in several brain areas of fully kindled rats. During the interictal period, kindled rats showed lower extracellular levels of dopamine when compared with those obtained in the control group under basal conditions, a situation that was not modified when an afterdischarge was evoked. Hippocampal perfusion of sulpiride, a D2 receptor antagonist, enhanced dopamine release, which was more evident when an afterdischarge was induced in kindled rats. In addition, sulpiride perfusion was associated with longer seizure duration. Functional autoradiography experiments revealed increased [(35)S]GTPγS incorporation as a consequence of D2-like receptor activation in different brain areas of fully kindled animals, including the ventral hippocampus. The present study reveals that hippocampal kindling is associated with alterations in dopamine release and D2-like receptor-induced neurotransmission.

Strong anticonvulsant effect of thalidomide on amygdaloid kindling.

Thalidomide was synthesized more than 50 years ago as hypnotic sedative with unique pharmacologic properties. Recently, we have described a notorious anticonvulsant effect of thalidomide on pentylenetetrazole-induced seizures. Here, we report the results of thalidomide administration on amygdaloid kindling. A total of 100 male Wistar rats were implanted with brain electrodes in the basolateral amygdaloid nucleus and the sensory motor cortex. After surgery the animals received a daily electric stimulus through the amygdaline electrode (500 µA intensity, 60 Hz frequency, 1 ms duration) until seizures appeared. The following treatment groups were made: (a) controls; (b) rats treated daily with thalidomide (10 mg/kg) or with topiramate (80 mg/kg); (c) rats treated with different doses of thalidomide. Significant reduction in the after-discharge and retard of behavioral stages were observed in rats treated with thalidomide or with topiramate as compared with controls (p<0.01): Also, a similar anticonvulsant outcome of thalidomide therapy was obtained with doses of either 2.5, 5, 10 or 50 mg/kg; at 100 mg/kg all epileptic activity was suppressed. Anticonvulsant efficacy of thalidomide was superior in most parameters than that obtained with topiramate. In amygdaloid kindling, which simulates human epilepsy characterized by focal seizures secondarily generalized, low doses of thalidomide display strong anticonvulsant properties.

Novel long-term anticonvulsant treatment with gabapentin without causing memory impairment in mice.

We previously reported that administration of a single dose of gabapentin (GBP) immediately after training improves memory of mice in an inhibitory avoidance task (IA), whereas GBP administered repeatedly for 7 days impairs memory. This is in accordance with the observation that long-term clinical treatment with GBP may be associated with adverse cognitive side effects. In the present work we used a GBP-loaded poly(epsilon-caprolactone) implant, allowing controlled release of the drug and maintenance of constant plasma levels over 1 week. When GBP-loaded implants were inserted subcutaneously into mice, immediately after training in the IA task, memory consolidation was enhanced. Moreover, GBP released from implants had an anticonvulsant action against pentylenetetrazole-induced seizures. These results suggest that maintenance of stable GBP plasma levels could protect against seizures without causing memory impairment. Hence, the adverse cognitive effects might be avoided by stabilizing plasma levels of the drug.

Effect of repeated administration of Annona diversifolia Saff. (ilama) extracts and palmitone on rat amygdala kindling.

Annonas are consumed as fresh fruits, but, because of their effects on the central nervous system, are also used in folk medicine. The effect on rat amygdala kindling of repeated administration of Annona diversifolia hexane (100mg/kg IP or PO) and ethanol (100mg/kg, PO) leaf extracts and palmitone (10mg/kg, IP) was determined. Electrographic and/or behavioral changes were monitored during kindling-induced seizures 60minutes after treatments. Antiepileptic efficacy was evaluated with respect to afterdischarge (AD) duration, spike frequency, and/or behavioral seizure activity. Oral administration of both extracts significantly decreased spike frequency, whereas intraperitoneally administered hexane extract and palmitone only reduced AD duration. Hexane extract and palmitone exhibited anticonvulsant properties and delayed establishment of a kindling state as observed with diazepam (0.3mg/kg IP). These results reinforce the anticonvulsant properties of this plant, and palmitone and other constituents are responsible for the pharmacological effects.

Chelatable zinc modulates excitability and seizure duration in the amygdala rapid kindling model.

Zinc is present in high concentration in many structures of the limbic circuitry, however the role of zinc as a neuromodulator in such synapses is still uncertain. In this work, we verified the effects of zinc chelation in an animal model of epileptogenesis induced by amygdala rapid kindling. The basolateral amygdala was electrically stimulated ten times per day for 2 days. A single stimulus was applied on the third day. Stimulated animals received injections of PBS or the zinc chelator diethildythiocarbamate acid (DEDTC) before each stimulus series. Animals were monitored with video-EEG and were perfused 3h after the last stimulus for subsequent neo-Timm and Fluoro-Jade B analysis. Zinc chelation decreased the duration of both behavioral seizures and electrical after-discharges, and also decreased the EEG spikes frequency, without changing the progression of behavioral seizure severity. These results indicate that the zinc ion may have a facilitatory role during kindling progression.