Kindling-induced Learning Deficit Research Articles

Effects of a lyophilized aqueous extract of Feretia apodanthera Del. (Rubiaceae) on pentylenetetrazole-induced kindling, oxidative stress, and cognitive impairment in mice

Feretia apodanthera Del. (Rubiaceae) is extensively used in ethnomedicine in Cameroon and Nigeria for epilepsy, febrile convulsions, and rheumatic pains and for enhancing cognitive performance. The aim of the present study was to examine the effects of a lyophilized aqueous extract of F. apodanthera on the course of kindling development, kindling-induced learning deficit, oxidative stress markers, and cholinesterase activity in pentylenetetrazole (PTZ)-kindled mice. Pentylenetetrazole, 30mg/kg, induced kindling in mice after 30.00±1.67days. The aqueous extract of F. apodanthera showed dose-dependent antiseizure effects. Feretia apodanthera (150–200mg/kg) significantly increased the latency to myoclonic jerks, clonic seizures, and generalized tonic–clonic seizures. The extract also improved the seizure score and decreased the number of myoclonic jerks. Pentylenetetrazole kindling induced significant oxidative stress and cognitive impairment which were reversed by pretreatment with F. apodanthera in a dose-dependent manner. The significant decrease in cholinesterase activity observed in the PTZ-kindled mice was reversed by pretreatment with the F. apodanthera extract. The results indicated that pretreatment with the aqueous extract of F. apodanthera antagonizes seizures, oxidative stress, and cognitive impairment in PTZ-kindled mice. The aqueous extract of F. apodanthera also showed anxiolytic activities, but the inhibition of memory impairment was not attributed to the anxiolytic activities of the plant. These results thus suggest the potential of F. apodanthera as an adjuvant in epilepsy both to prevent seizures as well as to protect against seizure-induced oxidative stress and memory impairment.

Kindling-induced learning deficiency and possible cellular and molecular involved mechanisms

Hippocampus learning disturbance is a major symptom of patients with seizure, hence hippocampal dysfunction has essential role in worsening the disease. Hippocampal formation includes neurons and myelinated fibers that are necessary for acquisition and consolidation of memory, long-term potentiation and learning activity. The exact mechanism by which seizure can decrease memory and learning activity of hippocampus remains unknown. In the present study, electrical kindling-induced learning deficit in rats was evaluated by Morris water maze (MWM) test. The hippocampus was removed and changes in neurons and myelin sheaths around hippocampal fibers were investigated using histological and immunohistochemical methods. Demyelination was assessed by luxol fast blue staining, and immunohistological staining of myelin-binding protein (MBP). The TUNEL assay was used for evaluation of neuronal apoptosis and the glial fibriliary acetic protein (GFAP) was used for assessment of inflammatory reaction. The results indicated that electrical kindling of hippocampus could induce deficiency in spatial learning and memory as compared to control group. In addition, electrical kindling caused damage to the myelin sheath around hippocampal fibers and produced vast demyelination. Furthermore, an increase in the number of apoptotic cells in hippocampal slices was observed. In addition, inflammatory response was higher in kindled animals as compared to the control group. The results suggested that the decrease in learning and memory in kindled animals is likely due to demyelination and augmentation in apoptosis rate accompanied by inflammatory reaction in hippocampal neurons of kindled rats.

Effect of Centella asiatica on pentylenetetrazole-induced kindling, cognition and oxidative stress in rats

Cognitive impairment in epileptics may be a consequence of the epileptogenic process as well as antiepileptic medication. Thus, there is a need for drugs, which can suppress epileptogenesis as well as prevent cognitive impairment. In the present study, the effect of aqueous extract of Centella asiatica (CA) (100 and 300 mg/kg), an Indian medicinal plant known to possess antiepileptic, cognitive-enhancing and antioxidant property, was evaluated on the course of kindling development, kindling-induced learning deficit and oxidative stress markers in pentylenetetrazole (PTZ) kindled rats. Male Wistar rats were injected PTZ (30 mg/kg ip) once every alternate day (48±2 h) until the development of the kindling. Passive avoidance test and spontaneous locomotor activity were carried out 24 and 48 h after the last administration of PTZ, while the oxidative stress parameters (malondialdehyde [MDA] and glutathione) were carried out in the whole brain upon completion of the behavioral assessment. The administration of CA (300 mg/kg orally) decreased the PTZ-kindled seizures and showed improvement in the learning deficit induced by PTZ kindling as evidenced by decreased seizure score and increased latencies in passive avoidance behavior. However, low dose of the CA (100 mg/kg) showed improvement only in the learning deficit due to the kindling and failed to improve the seizure score. The findings suggest the potential of aqueous extract of CA as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment.

Effects of nicardipine, an antagonist of l-type voltage-dependent calcium channels, on kindling development, kindling-induced learning deficits and hippocampal potentiation phenomena

Kindling is considered to be a useful experimental model for investigating drug effects on the convulsive component of epilepsy and related alterations at the behavioural level. It was demonstrated that pentylenetetrazol (PTZ)-kindled rats show diminished learning performance in shuttle-box training. We used this model to study the influence of nicardipine, an antagonist of l-type voltage-dependent calcium channels, on kindling seizure development as well as related learning impairments. Additionally, we tested the influence of nicardipine on kindling-induced potentiation, a special form of long-term enhancement of evoked potentials in the dentate gyrus after kindling. Therefore, monosynaptic evoked field potentials in the dentate area upon test stimuli to the perforant pathway were recorded in freely moving kindled and control rats at different times after injection of PTZ. The results indicate that the blockade of l-type voltage-dependent Ca 2+-channels during the kindling procedure attenuates PTZ-kindling, antagonizes a kindling-induced learning deficit in an active avoidance test and decreases a novel form of kindling-related potentiation, the long-lasting amplitude enhancement of the monosynaptic evoked field potential in the dentate gyrus after injection of a small test dose of PTZ. This potentiation can also be prevented in kindled animals by nicardipine injection in an acute experiment.

Effects of piracetam on pentylenetetrazol-kindling development, hippocampal potentiation phenomena and kindling-induced learning deficit.

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.

Involvement of delta-opioid receptors in pentylenetetrazol kindling development and kindling-related processes in rats.

The role of delta-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 delta-opioid receptors by intracerebroventricular administration of naltrindole (10 nmol/5 microl) 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. Summarizing the results, an involvement of the delta-opioid system in mechanisms underlying chemical kindling was clearly demonstrated. Interactions of endogenous opioid systems with glutamatergic transmission were suggested.

Piracetam prevents pentylenetetrazol kindling-induced neuronal loss and learning deficits

The effect of the nootropic drug piracetam (100 mg/kg) on kindled seizures, kindling-induced learning deficits, and histological alterations due to changes in central excitability was investigated in Wistar rats. The animals were kindled by repeated i.p. injections of an initially subconvulsive dose of pentylenetetrazol (PTZ). As a control, piracetam or physiological saline was given 60 minutes before PTZ. Twenty-four hours after completion of kindling the rats were tested in a shuttle-box paradigm. Seven days after the final kindling injection, the animals received a challenge dose of PTZ. Finally, the brains of the rats were processed for histological investigation. Pentylenetetrazol-kindled animals showed increasing seizure scores, and a learning deficit in the shuttle-box. Piracetam had no effect either on kindling development or on the reaction to a challenge dose of PTZ, but it protected the animals against the kindling-induced reduction of learning performance. The substance had no effect on learning performance in control animals. In distinct hippocampal structures, a neuronal cell loss was found in kindled rats. Interestingly, piracetam counteracted this damage efficaciously. The effects of piracetam are discussed in terms of its cytoprotective action. It is suggested that a coadministration of piracetam with clinically used antiepileptic drugs might be useful in antiepileptic therapy.

Antiepileptic drugs — Their effects on kindled seizures and kindling-induced learning impairments

Many epileptic patients suffer from cognitive impairments. These impairments may be a consequence of the epileptogenic process and/or antiepileptic medication. Kindling is considered a useful experimental model to investigate drug effects on both the convulsive component of epilepsy and related alterations at the behavioral level. In our experiments, kindling was induced by repeated injections of pentylenetetrazol (PTZ). To test the effect of antiepileptic drugs on kindled seizures and kindling-induced learning deficits we injected ethosuximide, dipropylacetate, and phenobarbital prior to each kindling stimulation or after kindling completion, and tested these animals in a shuttle-box paradigm. Dipropylacetate and phenobarbital suppressed the development of motor seizures and counteracted the learning deficit. Although ethosuximide had a clear effect on kindled seizures, the learning deficit occurred in kindled rats. This suggests that AEDs effects on kindled seizures are not correlated with the elemination of deficits in the field of cognition.

Nootropic drugs have different effects on kindling-induced learning deficits in rats

Kindling represents an accepted model of human epileptogenesis. Furthermore, it has been demonstrated that kindled rats show a diminished learning performance in an active avoidance task. In our study we administered different nootropic drugs to kindled rats to test their effects on learning a two-way active avoidance task in the shuttle-box. Kindling was induced by repeated intraperitoneal injections of 45 mg kg-1 pentylenetetrazol (PTZ) once every 48 h. The substances vinpocetine (0.1 and 1.0 mg kg-1), methylglucamin orotate (225 and 450 mg kg-1), piracetam (100 mg kg-1), and meclofenoxate (100 mg kg-1) were administered during kindling development and after kindling completion prior to each session in the learning experiment. The nootropic drugs had little if any effect on severity of seizures. Concerning their effect on learning the substances each acted in a specific manner. Methylglucamin orotate enhanced the learning deficit induced by kindling. Meclofenoxate injected prior to the kindling stimulation was ineffective, whereas administration prior to the learning test improved the learning performance effectively. A complementary action was shown in experiments with vinpocetine. Only piracetam prevented the occurrence of kindling-induced learning deficits regardless the administration schedule.

PK/PD modelling of the anticonvulsant and EEG effects of phenytoin

Many epileptic patients suffer from cognitive impairments. These impairments may be a consequence of the epileptogenic process and/or antiepileptic medication. Kindling is considered a useful experimental model to investigate drug effects on both the convulsive component of epilepsy and related alterations at the behavioral level. In our experiments, kindling was induced by repeated injections of pentylenetetrazol (PTZ). To test the effect of antiepileptic drugs on kindled seizures and kindling-induced learning deficits we injected ethosuximide, dipropylacetate, and phenobarbital prior to each kindling stimulation or after kindling completion, and tested these animals in a shuttle-box paradigm. Dipropylacetate and phenobarbital suppressed the development of motor seizures and counteracted the learning deficit. Although ethosuximide had a clear effect on kindled seizures, the learning deficit occurred in kindled rats. This suggests that AEDs effects on kindled seizures are not correlated with the elemination of deficits in the field of cognition.

Gabaergic control of aggressive behaviours in rats

Many epileptic patients suffer from cognitive impairments. These impairments may be a consequence of the epileptogenic process and/or antiepileptic medication. Kindling is considered a useful experimental model to investigate drug effects on both the convulsive component of epilepsy and related alterations at the behavioral level. In our experiments, kindling was induced by repeated injections of pentylenetetrazol (PTZ). To test the effect of antiepileptic drugs on kindled seizures and kindling-induced learning deficits we injected ethosuximide, dipropylacetate, and phenobarbital prior to each kindling stimulation or after kindling completion, and tested these animals in a shuttle-box paradigm. Dipropylacetate and phenobarbital suppressed the development of motor seizures and counteracted the learning deficit. Although ethosuximide had a clear effect on kindled seizures, the learning deficit occurred in kindled rats. This suggests that AEDs effects on kindled seizures are not correlated with the elemination of deficits in the field of cognition.