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Ashish Dhir - One of the best experts on this subject based on the ideXlab platform.
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pentylenetetrazol ptz Kindling model of epilepsy
Current protocols in protein science, 2012Co-Authors: Ashish DhirAbstract:This unit describes a protocol to perform chemical Kindling in mice. Kindling is a chronic animal model of epilepsy that has been extensively studied to understand the process of epileptogenesis and discover novel anti-epileptic compounds. Kindling is a phenomenon where a sub-convulsive stimulus (either chemical or electrical), if applied repetitively and intermittently, will ultimately lead to the generation of full-blown convulsions. Kindling can be induced either by (1) electrical stimulation of different brain regions (electrical Kindling) or (2) using various chemical agents (chemical Kindling). This unit discusses in detail the methodology to execute pentylenetetrazol (PTZ; a GABAA receptor antagonist)–induced chemical Kindling in mice. PTZ is administered chronically at a sub-convulsive dose for a number of days. Seizure score is calculated after each PTZ injection. The effect of test/reference compounds can be tested by administering them either prior to the initiation of Kindling (pre-Kindling phase) or after animals are fully kindled (post-Kindling phase). Curr. Protoc. Neurosci. 58:9.37.1-9.37.12. © 2012 by John Wiley & Sons, Inc. Keywords: epilepsy; chemical Kindling; mice; pentylenetetrazol
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pentylenetetrazol ptz Kindling model of epilepsy
Current protocols in protein science, 2012Co-Authors: Ashish DhirAbstract:This unit describes a protocol to perform chemical Kindling in mice. Kindling is a chronic animal model of epilepsy that has been extensively studied to understand the process of epileptogenesis and discover novel anti-epileptic compounds. Kindling is a phenomenon where a sub-convulsive stimulus (either chemical or electrical), if applied repetitively and intermittently, will ultimately lead to the generation of full-blown convulsions. Kindling can be induced either by (1) electrical stimulation of different brain regions (electrical Kindling) or (2) using various chemical agents (chemical Kindling). This unit discusses in detail the methodology to execute pentylenetetrazol (PTZ; a GABA(A) receptor antagonist)-induced chemical Kindling in mice. PTZ is administered chronically at a sub-convulsive dose for a number of days. Seizure score is calculated after each PTZ injection. The effect of test/reference compounds can be tested by administering them either prior to the initiation of Kindling (pre-Kindling phase) or after animals are fully kindled (post-Kindling phase).
Axel Becker - One of the best experts on this subject based on the ideXlab platform.
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pentylenetetrazol Kindling in mice overexpressing heat shock protein 70
Naunyn-schmiedebergs Archives of Pharmacology, 2007Co-Authors: Susanne Ammontreiber, Gisela Grecksch, Volker Höllt, Charalampos Angelidis, Patra Vezyraki, Axel BeckerAbstract:Kindling induced by the convulsant pentylenetetrazol (PTZ) is an accepted model of primary generalized epilepsy. Because seizures represent a strong distressing stimulus, stress-induced proteins such as heat shock proteins might counteract the pathology of increased neuronal excitation. Therefore, the aim of the present study was to determine whether PTZ Kindling outcome parameters are influenced by heat shock protein 70 (Hsp70) overexpression in Hsp70 transgenic mice as compared to the respective wild-type mice. Kindling was performed by nine intraperitoneal injections of PTZ (ED16 for induction of clonic–tonic seizures, every 48 h); control animals received saline instead of PTZ. Seven days after the final injection, all mice received a PTZ challenge dose. Outcome parameters included evaluation of seizure stages and overall survival rates. In addition, histopathological findings such as cell number in hippocampal subfields CA1 and CA3 were determined. The onset of the highest convulsion stage was delayed in Hsp70 transgenic mice as compared to wild-type mice, and overall survival during Kindling was improved in Hsp70 transgenic mice as compared to wild-type mice. In addition, a challenge dose after termination of Kindling produced less severe seizures in Hsp70 transgenic mice than in wild-type mice. PTZ Kindling did not result in significant subsequent neuronal cell loss in CA1 or CA3 neither in wild-type mice nor in the Hsp70 transgenic mice. The results of the present experiments clearly demonstrate that overexpression of Hsp70 exerts protective effects regarding seizure severity and overall survival during PTZ Kindling. In addition, the decreased seizure severity in Hsp70 transgenic mice after a challenge dose suggests an interference of Hsp70 with the developmental component of Kindling.
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Group I metabotropic glutamate receptors interfere in different ways with pentylenetetrazole seizures, Kindling, and Kindling-related learning deficits
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004Co-Authors: Raghavendra Y. Nagaraja, Helmut Schroeder, Gisela Grecksch, Klaus G. Reymann, Axel BeckerAbstract:LY 367385 (mGluR1) and MPEP (mGluR5), which are group I metabotropic glutamate receptor (mGluR) antagonists, were used to investigate their effects on pentylenetetrazole (PTZ) seizures, Kindling, and Kindling-related learning deficits. Both substances showed anticonvulsant efficacy against seizures induced by lower doses of PTZ (40 mg/kg), but they were ineffective in counteracting seizures evoked by higher PTZ doses. When these substances were given in the course of Kindling induction, LY significantly depressed the progression of kindled seizure severity. In contrast, MPEP was ineffective in this experiment. Treatment with either LY or MPEP did not modify the reaction to challenge dose of PTZ. Kindling results in a worsening of shuttle-box learning. LY improved shuttle-box learning when administered in the course of Kindling development or when given prior to the learning experiment. This suggests protective and restorative effectiveness. In contrast, MPEP was only effective on the learning performance of kindled rats when given prior to the shuttle-box experiment, which demonstrates restorative effectiveness. Kindling is associated with an increase in glutamate binding. LY counteracted this increase whereas MPEP was ineffective. It was concluded that mGluR1 and mGluR5 play a specific role in the convulsive component of Kindling. The beneficial action of the antagonists on Kindling-induced impairments in shuttle-box learning may be associated with their effect on glutamatergic synaptic activity.
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Involvement of δ-opioid receptors in pentylenetetrazol Kindling development and Kindling-related processes in rats
Naunyn-Schmiedeberg's Archives of Pharmacology, 1999Co-Authors: Gisela Grecksch, Axel Becker, Helmut Schroeder, Volker HölltAbstract:The role of δ-opioid receptors on the development of Kindling induced by the convulsant pentylenetetrazol (37.5 mg kg–1 i.p.) was investigated in rats. Besides the seizure development, the Kindling induced enhancement of glutamate binding and the Kindling-induced learning deficit were examined. A clear depression of Kindling development by blocking of δ-opioid receptors by intracerebroventricular administration of naltrindole (10 nmol/5 µl) was found. In an acute convulsion test performed 8 days after Kindling completion, animals pretreated with naltrindole during Kindling induction showed lower seizure stages compared to saline-pretreated kindled animals. The Kindling-induced increase in hippocampal glutamate binding was completely prevented by naltrindole, whereas the Kindling-induced learning deficit was not influenced. The learning performance of control animals pretreated with naltrindole was very low. It was hypothesized that the various consequences of Kindling induction could be influenced separately.
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Strain differences in pentylenetetrazol-Kindling development and subsequent potentiation effects.
Brain Research, 1997Co-Authors: Axel Becker, Manfred Krug, Helmut SchröderAbstract:Abstract Rats from two different strains, i.e. Wistar rats and Lister hooded rats, were investigated for their ability to acquire the Kindling syndrome. After having received 13 Kindling stimulations (injection of pentylenetetrazol), the animals were tested for subsequent alterations in induction and maintenance of hippocampal long-term potentiation (LTP) and, moreover in glutamate binding. It was found that rats from both strains did not differ in the response to the initial injection of pentylenetetrazol (PTZ) and the amplitude of the population spike. This suggests that some aspects of basic central excitability are equivalent. Wistar rats acquired the Kindling syndrome rapidly whereas seizure outcome was poor in Lister rats. As regards hippocampal LTP, the population spike was only dramatically increased in Wistar rats after Kindling completion. Glutamate binding was not altered in animals from the Lister strain. The results suggest that changes in glutamate binding and the increase in the population spike are characteristic consequences of Kindling.
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Effect of age on pentylenetetrazol-Kindling and Kindling-induced impairments of learning performance
Pharmacology Biochemistry and Behavior, 1997Co-Authors: Gisela Grecksch, Axel Becker, Christine RaucaAbstract:Epileptogenesis during ontogeny may not be linearly related to time. It is known that the behavioral manifestations of seizures are age-dependent, but more research is needed to clarify ontogenetic aspects of epilepsies and related alterations, including cognitive deficits. Kindling is an accepted animal model for the study of the convulsive component of epilepsy and its consequences on behavior. Recently, we demonstrated an impairment in acquisition of a conditioned reaction in young adult kindled rats, using pentylenetetrazol (PTZ) as the Kindling stimulus. The present study was undertaken to investigate the dependence on age of alterations in the induction of PTZ Kindling in rats. We started the Kindling protocol in 4-, 6-, and 8-week- and 6-, 12-, 18-, and 24-month-old rats. The PTZ Kindling showed an age-dependent decrease in expression of convulsions. The diminished Kindling capacity was already seen in 6-month-old rats. In contrast, Kindling-related impairment effects on cognitive functions increased with age. Thus, the correlation between learning impairment and occurrence of tonic-clonic seizures that we had demonstrated in 8-week-old rats was abolished in older rats. On the other hand, when the Kindling procedure was started in 6-week-old rats, no impairment was found in fully kindled rats.
Gisela Grecksch - One of the best experts on this subject based on the ideXlab platform.
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pentylenetetrazol Kindling in mice overexpressing heat shock protein 70
Naunyn-schmiedebergs Archives of Pharmacology, 2007Co-Authors: Susanne Ammontreiber, Gisela Grecksch, Volker Höllt, Charalampos Angelidis, Patra Vezyraki, Axel BeckerAbstract:Kindling induced by the convulsant pentylenetetrazol (PTZ) is an accepted model of primary generalized epilepsy. Because seizures represent a strong distressing stimulus, stress-induced proteins such as heat shock proteins might counteract the pathology of increased neuronal excitation. Therefore, the aim of the present study was to determine whether PTZ Kindling outcome parameters are influenced by heat shock protein 70 (Hsp70) overexpression in Hsp70 transgenic mice as compared to the respective wild-type mice. Kindling was performed by nine intraperitoneal injections of PTZ (ED16 for induction of clonic–tonic seizures, every 48 h); control animals received saline instead of PTZ. Seven days after the final injection, all mice received a PTZ challenge dose. Outcome parameters included evaluation of seizure stages and overall survival rates. In addition, histopathological findings such as cell number in hippocampal subfields CA1 and CA3 were determined. The onset of the highest convulsion stage was delayed in Hsp70 transgenic mice as compared to wild-type mice, and overall survival during Kindling was improved in Hsp70 transgenic mice as compared to wild-type mice. In addition, a challenge dose after termination of Kindling produced less severe seizures in Hsp70 transgenic mice than in wild-type mice. PTZ Kindling did not result in significant subsequent neuronal cell loss in CA1 or CA3 neither in wild-type mice nor in the Hsp70 transgenic mice. The results of the present experiments clearly demonstrate that overexpression of Hsp70 exerts protective effects regarding seizure severity and overall survival during PTZ Kindling. In addition, the decreased seizure severity in Hsp70 transgenic mice after a challenge dose suggests an interference of Hsp70 with the developmental component of Kindling.
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Group I metabotropic glutamate receptors interfere in different ways with pentylenetetrazole seizures, Kindling, and Kindling-related learning deficits
Naunyn-Schmiedeberg's Archives of Pharmacology, 2004Co-Authors: Raghavendra Y. Nagaraja, Helmut Schroeder, Gisela Grecksch, Klaus G. Reymann, Axel BeckerAbstract:LY 367385 (mGluR1) and MPEP (mGluR5), which are group I metabotropic glutamate receptor (mGluR) antagonists, were used to investigate their effects on pentylenetetrazole (PTZ) seizures, Kindling, and Kindling-related learning deficits. Both substances showed anticonvulsant efficacy against seizures induced by lower doses of PTZ (40 mg/kg), but they were ineffective in counteracting seizures evoked by higher PTZ doses. When these substances were given in the course of Kindling induction, LY significantly depressed the progression of kindled seizure severity. In contrast, MPEP was ineffective in this experiment. Treatment with either LY or MPEP did not modify the reaction to challenge dose of PTZ. Kindling results in a worsening of shuttle-box learning. LY improved shuttle-box learning when administered in the course of Kindling development or when given prior to the learning experiment. This suggests protective and restorative effectiveness. In contrast, MPEP was only effective on the learning performance of kindled rats when given prior to the shuttle-box experiment, which demonstrates restorative effectiveness. Kindling is associated with an increase in glutamate binding. LY counteracted this increase whereas MPEP was ineffective. It was concluded that mGluR1 and mGluR5 play a specific role in the convulsive component of Kindling. The beneficial action of the antagonists on Kindling-induced impairments in shuttle-box learning may be associated with their effect on glutamatergic synaptic activity.
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Effects of piracetam on pentylenetetrazol-Kindling development, hippocampal potentiation phenomena and Kindling-induced learning deficit.
Naunyn-Schmiedeberg's Archives of Pharmacology, 1999Co-Authors: Heinz Rüthrich, Gisela Grecksch, Manfred KrugAbstract:Kindling is a generally accepted model for studying epilepsy development in the context of overexpression of processes of neuronal plasticity. In previous studies we have shown that establishment of Kindling by repeated application of subconvulsive doses of pentylenetetrazol (PTZ) also led to marked changes in hippocampal excitability and an impairment in learning behaviour. With the intention of further investigating the relationship between Kindling development, Kindling-induced changes in excitability and learning deficits, rats were chemically kindled under pretreatment with the nootropic drug piracetam. Furthermore, we tested acute piracetam effects on developed Kindling seizures, the learning deficit and potentiation effects. At the investigated dose piracetam did not influence the Kindling development. The Kindling-induced potentiation of hippocampal field potentials was significantly diminished in piracetam-pretreated rats. Piracetam acutely injected completely antagonized this potentiation effect. Piracetam brought about a significant improvement in impaired learning performance in rats pretreated during Kindling induction and acutely injected before the learning experiment, respectively. Possible correlations between the suppressing of the Kindling related potentiation in hippocampal structures by piracetam and its beneficial effect on learning impairment are discussed as antagonizing overexpression of potentiation in the course of Kindling.
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Involvement of δ-opioid receptors in pentylenetetrazol Kindling development and Kindling-related processes in rats
Naunyn-Schmiedeberg's Archives of Pharmacology, 1999Co-Authors: Gisela Grecksch, Axel Becker, Helmut Schroeder, Volker HölltAbstract:The role of δ-opioid receptors on the development of Kindling induced by the convulsant pentylenetetrazol (37.5 mg kg–1 i.p.) was investigated in rats. Besides the seizure development, the Kindling induced enhancement of glutamate binding and the Kindling-induced learning deficit were examined. A clear depression of Kindling development by blocking of δ-opioid receptors by intracerebroventricular administration of naltrindole (10 nmol/5 µl) was found. In an acute convulsion test performed 8 days after Kindling completion, animals pretreated with naltrindole during Kindling induction showed lower seizure stages compared to saline-pretreated kindled animals. The Kindling-induced increase in hippocampal glutamate binding was completely prevented by naltrindole, whereas the Kindling-induced learning deficit was not influenced. The learning performance of control animals pretreated with naltrindole was very low. It was hypothesized that the various consequences of Kindling induction could be influenced separately.
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Effect of age on pentylenetetrazol-Kindling and Kindling-induced impairments of learning performance
Pharmacology Biochemistry and Behavior, 1997Co-Authors: Gisela Grecksch, Axel Becker, Christine RaucaAbstract:Epileptogenesis during ontogeny may not be linearly related to time. It is known that the behavioral manifestations of seizures are age-dependent, but more research is needed to clarify ontogenetic aspects of epilepsies and related alterations, including cognitive deficits. Kindling is an accepted animal model for the study of the convulsive component of epilepsy and its consequences on behavior. Recently, we demonstrated an impairment in acquisition of a conditioned reaction in young adult kindled rats, using pentylenetetrazol (PTZ) as the Kindling stimulus. The present study was undertaken to investigate the dependence on age of alterations in the induction of PTZ Kindling in rats. We started the Kindling protocol in 4-, 6-, and 8-week- and 6-, 12-, 18-, and 24-month-old rats. The PTZ Kindling showed an age-dependent decrease in expression of convulsions. The diminished Kindling capacity was already seen in 6-month-old rats. In contrast, Kindling-related impairment effects on cognitive functions increased with age. Thus, the correlation between learning impairment and occurrence of tonic-clonic seizures that we had demonstrated in 8-week-old rats was abolished in older rats. On the other hand, when the Kindling procedure was started in 6-week-old rats, no impairment was found in fully kindled rats.
Margaret Fahnestock - One of the best experts on this subject based on the ideXlab platform.
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The cholinergic system modulates Kindling and Kindling‐induced mossy fiber sprouting
Synapse, 2002Co-Authors: Beth Adams, Liezanne Vaccarella, Margaret Fahnestock, Ronald J. RacineAbstract:In a previous study, our laboratory demonstrated that the intraventricular infusion of nerve growth factor (NGF) accelerated Kindling rates and enhanced mossy fiber sprouting in the absence of noticeable Kindling-associated neuronal loss. The purpose of the present study was to investigate whether these NGF effects were mediated via the cholinergic system. This study evaluated the effects of the cholinergic agonist pilocarpine and the cholinergic antagonist scopolamine on Kindling rates and Kindling-induced mossy fiber sprouting in adult rats. The results showed that pilocarpine accelerated Kindling rates and enhanced Kindling-induced mossy fiber sprouting in the CA3 region of the hippocampus, whereas scopolamine retarded Kindling rates and blocked Kindling-induced mossy fiber sprouting in the CA3 and IML regions. These findings suggest that the cholinergic system may contribute to the long-term structural and functional alterations that are characteristic of the kindled state. Moreover, these data provide support for the hypothesis that NGF infusions may mediate Kindling and Kindling-induced mossy fiber sprouting via regulation of the cholinergic system.
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a nerve growth factor peptide retards seizure development and inhibits neuronal sprouting in a rat model of epilepsy
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Kashif Rashid, Ronald J. Racine, J Stanisz, Gregory M Ross, C A Chapman, R J Riopelle, Margaret FahnestockAbstract:Abstract Kindling, an animal model of epilepsy wherein seizures are induced by subcortical electrical stimulation, results in the upregulation of neurotrophin mRNA and protein in the adult rat forebrain and causes mossy fiber sprouting in the hippocampus. Intraventricular infusion of a synthetic peptide mimic of a nerve growth factor domain that interferes with the binding of neurotrophins to their receptors resulted in significant retardation of Kindling and inhibition of mossy fiber sprouting. These findings suggest a critical role for neurotrophins in both Kindling and Kindling-induced synaptic reorganization.
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intraventricular administration of antibodies to nerve growth factor retards Kindling and blocks mossy fiber sprouting in adult rats
The Journal of Neuroscience, 1995Co-Authors: Kashif Rashid, Ronald J. Racine, K Le, K A Moore, J Stanisz, J Diamond, Margaret FahnestockAbstract:Repeated subconvulsive electrical stimulation of certain areas of the forebrain leads to Kindling, a progressive and permanent amplification of evoked epileptiform activity, which is a model for human temporal lobe epilepsy. Recent studies have shown that Kindling induces synthesis of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) but not neurotrophin-3 (NT-3) in the hippocampus and cortex. Kindling also elicits mossy fiber sprouting and functional synaptogenesis in the supragranular layer, the hilus, and the CA3 region of the hippocampus. Intraventricular administration of antibodies to NGF has been shown to effectively block septohippocampal sprouting in the adult rat, and has been reported to retard amygdaloid Kindling. In the present study, we have investigated the possible role of NGF in both Kindling and Kindling-associated sprouting. We have confirmed a Kindling-induced sprouting of the mossy fibers into the stratum oriens of the CA3 region of the hippocampus, utilizing a new semiquantitative method of analysis based on Timm staining. Previous studies found no overt signs of hippocampal damage with this Kindling paradigm, indicating that the increased Timm staining likely reflects a purely activity-induced sprouting. Intraventricular infusion of affinity-purified anti-NGF IgGs (which cross-react with NT-3 but not BDNF) resulted in both significant retardation of Kindling and inhibition of the Kindling-induced mossy fiber sprouting. The findings suggest a role for NGF in both these phenomena.
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Kindling, Neurotrophins and Axon-Guidance Factors
Advances in Behavioral Biology, 1Co-Authors: Ronald J. Racine, Margaret FahnestockAbstract:Graham Goddard1 initially introduced Kindling as a model for memory. Although most frequently utilized as an epilepsy model, particularly for temporal lobe epilepsy, Kindling is occasionally used as a model for drug-induced plasticity, slowly developing neuropathologies other than epilepsy, and a variety of structural reorganizations of brain circuitry.2,3 Since our interest in the Kindling phenomenon (and other models of epilepsy) is largely driven by our interest in neural plasticity, we have chosen to focus on Kindling-induced neuronal reorganization. These Kindling-induced effects may not have much relevance for epilepsy, but they are themselves interesting and potentially important phenomena and provide an excellent model for the study of mechanisms of activity-dependent neural growth.
Javad Mirnajafizadeh - One of the best experts on this subject based on the ideXlab platform.
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comparison between standard protocol and a novel window protocol for induction of pentylenetetrazol kindled seizures in the rat
Epilepsy Research, 2013Co-Authors: Mahnaz Davoudi, Amir Shojaei, Mohammad Javan, Mohammad Reza Palizvan, Javad MirnajafizadehAbstract:Summary Experimental models of epilepsy, including pentylenetetrazol (PTZ) chemical Kindling, are very important in studying the pathophysiology of epilepsy. The aim of the present study was to provide behavioral, electrophysiological and molecular evidences to confirm the similarities between standard and a modified protocol named window- (win-) PTZ Kindling method. Standard PTZ Kindling model was induced by injection of PTZ (37.5mg/kg) every other days. In win-PTZ Kindling method, animals received 4 initial PTZ injections and the time of 3 last PTZ injections were determined according to the number of PTZ injections in standard PTZ Kindling model. The behavioral signs of kindled seizures were observed for 20min after each PTZ injection. Field potential recordings were done from the dentate gyrus granular cells following perforant path stimulation. In addition, the expression of γ 2 subunit of GABA A receptor, NR 2 A subunit of NMDA receptor, adenosine A 1 receptor, α-CaMKII and GAP-43 were evaluated in the hippocampus and dentate gyrus using RT-PCR technique. All the animals in win-PTZ Kindling method group achieved fully kindled state after 3 last PTZ injections. There was no significant difference in population spike amplitude and expression of the mentioned genes during Kindling acquisition between standard PTZ Kindling model and win-PTZ Kindling method. The similarities in electrophysiological and molecular parameters remained after 8 days post fully kindled state. Obtained data showed the similarities between this win-PTZ Kindling method and standard PTZ Kindling model. Thus, it may be suggested that not all PTZ injections are need for induction of PTZ induced fully kindled state.
