Pro-epileptic effects of the cannabinoid receptor antagonist SR141716 in a model of audiogenic epilepsy

Endocannabinoid system and its CB1 receptors are suggested to provide endogeneous protection against seizures. The present study examines whether CB1 receptors contribute to resistance to seizures and kindling epileptogenesis in a model of audiogenic epilepsy. Three groups of Wistar rats were used: rats unsusceptible to audiogenic seizures, rats with acquired resistance to audiogenic seizures and rats with reproducible audiogenic running seizures.Chronic treatment with the CB1 receptor antagonist SR141716 (5 daily dosing of 30 mg/kg) did not change innate resistance to audiogenic seizures in non-epileptic rats but reverted acquired seizure resistance in rats which lost their epileptic sensitivity with repeated testing. In the latter rats, audiogenic running seizures reappeared for at least two weeks after the end of treatment. In rats with reproducible seizure response, acutely, SR lengthened audiogenic seizures due to prolongation or appearance, de novo, of post-running limbic clonus without any effect on running seizure per se. This limbic component mimicked audiogenic kindling and indicated propagation of sound-induced brainstem seizure to the limbic forebrain. After chronic SR administration the incidence of the limbic clonus remained to be increased for at least two weeks.The present study supports the hypothesis about a role of CB1 receptors in endogeneous anticonvulsive mechanisms of the brain.     

The effects of brain-irradiation-induced decreases in hippocampal mitotic activity on flurothyl-induced epileptogenesis in adult C57BL/6J mice

Previous studies have demonstrated that seizures are potent inducers of mitotic activity in the rodent hippocampus. The role of this mitotic activity in epileptogenesis currently remains unknown. In the present study, we investigated the effect of alterations in hippocampal mitotic activity on changes in seizure threshold and phenotype using flurothyl kindling. In flurothyl kindling, eight repeated flurothyl-induced generalized forebrain (clonic) seizures result in a rapid, progressive, and permanent lowering of the generalized seizure threshold in mice and in a slowly evolving increase in the percentage of animals expressing forebrain-brain stem (clonic-tonic) seizures when reexposed to flurothyl following a 2- to 4-week stimulation-free period. Therefore, flurothyl kindling serves as an excellent model for evaluating mechanisms of generalized seizure threshold and seizure propagation. To investigate this relationship between hippocampal mitotic activity and epileptogenesis, mice were given brain irradiation, focused mainly on the hippocampus, bilaterally, and were exposed to the flurothyl kindling model of epileptogenesis. Brain irradiation virtually eliminated all basal and seizure-induced mitotic activity in the hippocampal dentate gyrus of mice. In addition, animals that underwent irradiation and flurothyl kindling did not differ from control mice on measures of seizure threshold (threshold induction and maintenance) and seizure phenotype. Overall, these results suggest that seizure-induced increases in mitotic activity in the hippocampal dentate gyrus are not directly related to the processes that underlie the shift in behavioral seizure phenotype or in either the induction or the maintenance of lowered seizure threshold that is observed in this flurothyl model of epileptogenesis.     

Audiogenic kindling in Wistar and WAG/Rij rats: kindling-prone and kindling-resistant subpopulations

Purpose: Audiogenic kindling (AK) is a model of naturally occurring epileptogenesis triggered by repeated sound stimulation of rats genetically prone to audiogenic seizures. It is accepted that limbic seizure networks underlie progressive changes in behavioral seizure pattern during AK. The present study investigated AK progression in rats susceptible and unsusceptible to absence seizures. Methods: Progression of AK as indicated by an appearance and intensification of limbic clonus was examined in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats with genetic absence epilepsy and in Wistar rats. Results: Subpopulations of kindling‐prone and kindling‐resistant rats were found in both Wistar and WAG/Rij strains. Despite identical seizure responses to the first sound stimulation, AK progression dramatically differed between the two subpopulations. AK‐prone rats exhibited rapid kindling development up to maximal stage‐5 severity. In AK‐resistant rats, limbic clonus did not appear after 30 stimulations or if it appeared, it did not progress beyond stage 2. The proportions of AK‐prone and AK‐resistant animals within Wistar and WAG/Rij strains were similar. Comparison of Wistar and WAG/Rij rats within the kindling‐prone and kindling‐resistant groups did not reveal a significant strain effect on AK progression. However, within the WAG/Rij strain, a significantly higher incidence of absence seizures was found in AK‐resistant rats compared to AK‐prone rats. Conclusions: The present study demonstrates that sensitivity to sound‐induced epileptogenesis differs dramatically within Wistar and WAG/Rij strains, whereas genetic susceptibility to absence seizures does not change AK progression significantly. It is supposed that an increased incidence of nonconvulsive seizures and resistance to kindling result from a common seizure modulating mechanism.     

Suppression of limbic motor seizures by electrical stimulation in thalamic reticular nucleus

Kindling is a model of temporal lobe epilepsy in which repeated electrical stimulations in limbic areas lead to progressive increase of seizure susceptibility, culminating in generalized convulsions and the establishment of a permanent epileptic syndrome. We studied here the effect of stimulations in the thalamic reticular nucleus (TRN) on the development of seizures and hippocampal hyperexcitability in kindling elicited from the ventral hippocampus in rats. Animals given 12 kindling stimulations per day with 30-min intervals for 4 consecutive days developed generalized convulsions on day 4. Stimulations in TRN delivered simultaneously with those in the hippocampus induced marked suppression of seizure generalization. Similarly, the number of generalized seizures and the duration of behavioral convulsions were reduced when rats subjected to 40 kindling stimulations with 5-min intervals during about 3 h were costimulated in the TRN. The anticonvulsant effect of TRN costimulation was detected also when rats were test-stimulated in the hippocampus at 24 h and 2 and 4 weeks after the initial 40 hippocampal stimulations. Our data provide the first evidence that TRN stimulations can act to suppress limbic motor seizures in hippocampal kindling and suggest a new approach for seizure control in temporal lobe epilepsy.     

Role of neurosteroids in catamenial epilepsy

Catamenial epilepsy is a menstrual cycle-related seizure disorder that affects up to 70% of women with epilepsy. Catamenial epilepsy is characterized by an increase in seizures during particular phases of the menstrual cycle. Three distinct patterns of catamenial epilepsy - perimenstrual, periovulatory, and inadequate luteal phase - have been described. Currently, there is no specific treatment for catamenial epilepsy. The molecular mechanisms involved in the pathophysiology of catamenial epilepsy are not well understood. Recent studies suggest that cyclical changes of ovarian hormones estrogens (proconvulsant) and progesterone (anticonvulsant) appear to play a key role in the genesis of catamenial seizures. Progesterone reduces seizure susceptibility partly through conversion to neurosteroids such as allopregnanolone, which enhances GABA(A) receptor function and thereby inhibits neuronal excitability. In animal models, withdrawal from chronic progesterone and, consequently, of allopregnanolone levels in brain, has been shown to increase seizure susceptibility. Natural progesterone therapy has proven effective in women with epilepsy. Moreover, neurosteroids have been shown to be very effective inhibitors of catamenial seizures in animal models. Thus, synthetic neuroactive steroids, such as ganaxolone, which are orally active and devoid of hormonal side effects, represent a novel treatment strategy for catamenial epilepsy. However, their clinical efficacy in catamenial epilepsy has yet to be explored. A greater understanding of the molecular mechanisms is clearly needed for designing effective treatment and prevention strategies of catamenial epilepsy in women at risk.     

Neurosteroids and epileptogenesis in the pilocarpine model: Evidence for a relationship between P450scc induction and length of the latent period

Purpose:   Cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) catalyzes the initial step in the biosynthesis of neurosteroids within the brain. We sought to determine which cells express P450cc and whether neurosteroids play a role in the regulation of epileptogenesis following pilocarpine-induced status epilepticus (SE).
Methods:   Rats experienced uninterrupted SE or SE terminated with diazepam at 60, 120, and 180 min. P450scc induction in CA3 hippocampus was determined by double immunolabeling with P450scc antiserum and monoclonal antibodies against GFAP (astrocytes), RIP (oligodendrocytes), or heme oxygenase-1 (microglia).
Results:   SE was associated with P450scc induction in many astrocytes and a small number of microglia and oligodendrocytes in the hippocampal CA3 strata radiatum and lacunosum-moleculare. The extent of P450scc induction increased with increasing SE duration. Paradoxically, increased P450scc induction in rats experiencing SE for 180 min or more was associated with the delayed onset of spontaneous recurrent seizures. Treatment with the 5α-reductase inhibitor finasteride (100 mg/kg/day for 25 days), which inhibits the synthesis of γ-aminobutyric acid (GABA)_A receptor modulating neurosteroids such as allopregnanolone, was associated with a significant reduction in time to the onset of spontaneous seizures in rats exposed to 180-min but not 90-min SE.
Discussion:   P450scc is induced by SE in a diverse population of hippocampal glia. Induction of P450scc is associated with the delayed onset of spontaneous seizures. Conversely, inhibition of neurosteroid synthesis accelerated the onset of spontaneous seizures, but only in animals exhibiting significant increases in P450scc. These findings suggest that induction of neurosteroid synthesis in reactive glial cells is associated with delayed onset of spontaneously recurrent seizures.     

The basic science of memory as it applies to epilepsy

Summary   The mechanisms of memory delineated by the model of long-term potentiation (LTP) are similar to those underlying epileptogenesis by kindling. Memory is impaired by seizures and epilepsy. High frequency neural activity is important in both memory formation and seizures. Both kindling and LTP are most effectively induced by high-frequency stimuli, involve synaptic facilitation, and share overlapping molecular mechanisms, such as N-methyl- d -aspartate (NMDA) receptor-induced calcium cascade and protein synthesis. The hippocampus contributes to both through its role in memory formation and its low seizure threshold.     

Antiepileptogenic effects of trilostane in the kainic acid model of temporal lobe epilepsy

Objective

Epileptogenesis after status epilepticus (SE) has a faster onset in rats treated to reduce brain levels of the anticonvulsant neurosteroid allopregnanolone with the 5α-reductase inhibitor finasteride; however, it still has to be evaluated whether treatments aimed at increasing allopregnanolone levels could result in the opposite effect of delaying epileptogenesis. This possibility could be tested using the peripherally active inhibitor of 3β-hydroxysteroid dehydrogenase/Δ^5-4 isomerase trilostane, which has been shown repeatedly to increase allopregnanolone levels in the brain.

Methods

Trilostane (50 mg/kg) was administered subcutaneously once daily for up to six consecutive days, starting 10 min after intraperitoneal administration of kainic acid (15 mg/kg). Seizures were evaluated by video-electrocorticographic recordings for 70 days maximum, and endogenous neurosteroid levels were assessed by liquid chromatography–electrospray tandem mass spectrometry. Immunohistochemical staining was performed to evaluate the presence of brain lesions.

Results

Trilostane did not alter the latency of kainic acid-induced SE onset or its overall duration. When compared to the vehicle-treated group, rats receiving six daily trilostane injections presented a remarkable delay of the first spontaneous electrocorticographic seizure and subsequent tonic–clonic spontaneous recurrent seizures (SRSs). Conversely, rats treated with only the first trilostane injection during SE did not differ from vehicle-treated rats in developing the SRSs. Notably, trilostane did not modify neuronal cell densities or the overall damage in the hippocampus. In comparison to the vehicle group, repeated administration of trilostane significantly decreased the activated microglia morphology in the subiculum. As expected, allopregnanolone and other neurosteroid levels were remarkably increased in the hippocampus and neocortex of rats treated for 6 days with trilostane, but pregnanolone was barely detectable. Neurosteroids returned to basal levels after a week of trilostane washout.

Significance

Overall, these results suggest that trilostane led to a remarkable increase in allopregnanolone brain levels, which was associated with protracted effects on epileptogenesis.     

Inter-ictal and post-ictal circulating levels of allopregnanolone,an anticonvulsant metabolite of progesterone,in epileptic children

Allopregnanolone belongs to a group of neuroactive steroid hormones, or neurosteroids, synthesized and acting within the brain and is as a potent endogenous positive modulator of GABA(A) receptor complex. Administration of allopregnanolone protects rats against pentylentetrazol, bicuculline, kainic acid, and picrotoxin-induced seizures. We investigated serum allopregnanolone levels in children with active epilepsy at pubertal Tanner's stage I (n=52). Blood specimens were collected at least 12 h after a seizure (inter-ictal). In a subgroup of patients (n=11), specimens were also collected within 30 min from a seizure attack (post-ictal). Healthy age-matched children (n=18) served as controls. Serum allopregnanolone was measured by radioimmunoassay using a polyclonal antiserum. The inter-ictal serum allopregnanolone levels in the epileptic children were not statistically different from those detected in the control group, whereas post-ictal levels were significantly higher than the inter-ictal ones (P=0.0001). In this subgroup of patients allopregnanolone levels decreased to the basal values during the following 12 h. Serum allopregnanolone levels may therefore reflect changes in neuronal excitability, and allopregnanolone appears to be a reliable circulating marker of epileptic seizures. It is possible that increased post-ictal serum levels of allopregnanolone may play a role in modulating neuronal excitability and may represent an endogenous mechanism of seizure control.     

Developmental Aspects of Epileptogenesis

Summary: Several factors may contribute to the propensity for the developing brain to have seizures and develop epilepsy. Hypersynchrony of neuronal circuits contributes to the seizure potential and several neurobiological features of the immature brain may support synchronized neuronal firing. The immature cerebral cortex and hippocampus have an increased density of synapses compared to adults and also a higher density of gap junctions and of excitatory amino acid receptors. Enhanced regenerative responses to injury in the developing brain may also contribute to the formation of abnormal hippocampal connections that support epilepsy. Molecular mechanisms that contribute to enhanced synaptic plasticity in the child's brain can also contribute to epileptogenesis in certain circumstances. The phenomenon of kindling, where repeated electrical stimulation of neuronal circuits leads to the development of epileptic seizures, is easily elicited in young animals. Longterm potentiation (LTP), where repeated synpatic stimulation leads to a reduced threshold for activation of that pathway and enhanced postsynaptic potentials, is much more robust in the immature cerebral cortex and may contribute to kindling and epileptogenesis. Age related enhancement of N-methyl d-asparatetype glutatmate receptors, which are important for the activity dependent plasticity in the developing brain, appears to participate in LTP. This information suggests that normal developmental features of synaptic development make the immature brain more excitable than the adult brain and may contribute to epileptogenesis.     

Clozapine inhibits limbic system kindling: Implications for antipsychotic action

Clozapine and haloperidol were tested for their ability to influence the acquisition of kindled seizures following electrical stimulation of the amygdala and ventral hippocampus. While haloperidol pretreatment did not alter kindling genesis from either limbic region, preexposure to clozapine delayed the rate at which kindling evolved. Anatysis of the number of seizure behaviors expressed during epileptogenesis revealed that clozapine produced a relative antagonism of seizure development arresting kindling at the stage-3 level. The kindling inhibition was dependent upon the daily administration of clozapine during the kindling process and was not evident after withdrawal from a chronic schedule of clozapine exposure. A subconvulsive dose of pilocarpine (80.0 mg/kg) produced an overall enhancement of kindling rate, a finding consistent with the excitatory role of acetylcholine (ACh) in kindling. Lower doses of pilocarpine (20.0 and 40.0 mg/kg) that did not alter seizure advancement partially antagonized the clozapine-elicited inhibition of amygdaloid kindling. Pilocarpine, however, did not affect the clozapine-induced increase in the number of stage-3 behaviors exhibited during amygdaloid kindling, suggesting that other neurochemical effects of clozapine, not related to its anticholinergic properties, modulate the kindling suppression. Clozapine's unique actions on limbic system sensitization were discussed in relation to its effectiveness as an antipsychotic agent.     

Anticonvulsant action of a non-competitive antagonist of NMDA receptors (MK-801) in the kindling model of epilepsy

Anticonvulsant action of MK-801, a novel non-competitive antagonist of N-methyl-d-aspartate (NMDA) receptors, was investigated in the kindling model of epilepsy in rats. The results obtained were as follows. (1) Both the seizure stage and afterdischarge duration of previously kindled seizures from the amygdala were significantly suppressed following systemic injection of MK-801 (0.25–4 mg/kg) in a dose-dependent manner. The maximum effects were observed between 2 and 4 h after the injection. (2) The MK-801 also showed significant anticonvulsant effedts on kindled seizures from the frontal cortex and the ventral and dorsal hippocampus. The efficacy however, significantly differed between these kindled sites. (3) Daily treatment of MK-801 (0.25 and 1 mg/kg) prior to each electrical stimulation of the amygdala significantly retarded kindling seizure development and increased the total amount of afterdischarge (accumulated AD) required to reach the first stage 5 seizure. During drug sessions of 1 mg/kg MK-801 for 19 days, all rats showed only partial seizures and the growth of afterdischarge was strongly prevented. (4) Pretreatment with reserpine did not antagonize the anticonvulsant effects of MK-801 on previously kindled seizures from the amydala, suggesting that the effects may not be mediated by catecholaminergic systems. These results indicate that MK-801 has potent anticonvulsant actions on kindled seizures from both limbic and cortical foci, the NMDA system may play a critical role in the seizure-triggering mechanism of kindling. The possible application of NMDA antagonists in clinical epilepsy is suggested.     

Proteomic identification of the involvement of the mitochondrial rieske protein in epilepsy

PURPOSE: Kindled seizures are widely used to model epileptogenesis, but the molecular mechanisms underlying the attainment of kindling status are largely unknown. Recently we showed that achievement of kindling status in the Sprague-Dawley rat is associated with a critical developmental interval of 25 +/- 1 days; the identification of this long, well-defined developmental interval for inducing kindling status makes possible a dissection of the cellular and genetic events underlying this phenomenon and its relation to normal and pathologic brain function. METHODS: By using proteomics on cerebral tissue from our new rat kindling model, we undertook a global analysis of protein expression in kindled animals. Some of the identified proteins were further investigated by using immunohistochemistry. RESULTS: We report the identification of a modified variant of the Rieske iron-sulfur protein, a component of the mitochondrial cytochrome bc1 complex, whose isoelectric point is shifted toward more alkaline values in the hippocampus of kindled rats. By immunohistochemistry, the Rieske protein is well expressed in the hippocampus, except in the CA1 subfield, an area of selective vulnerability to seizures in humans and animal models. We also noted an asymmetric, selective expression of the Rieske protein in the subgranular neurons of the dorsal dentate gyrus, a region implicated in neurogenesis. CONCLUSIONS: These results indicate that the Rieske protein may play a role in the response of neurons to seizure activity and could give important new insights into the molecular pathogenesis of epilepsy.     

Amygdaloid kindling and cerebrospinal cyclic nucleotides

The kindling model of experimental epilepsy is characterized by a persistent seizure pattern and long-lasting seizure susceptibility without associated tissue damage. In order to examine the relationship between CSF cyclic nucleotides and epilepsy. CSF cAMP and cGMP were measured before and after kindling, or after electrically induced seizures. Cyclic AMP and cGMP levels in cisternal CSF decreased significantly 1 week after the amygdaloid kindling. This finding suggests decreased levels of brain cAMP and cGMP in this type of epileptogenesis. A slight increase in CSF cyclic nucleotides concentrations was found after triggering both partial and generalized seizures. There was, however, no difference in increase of cAMP and cGMP levels between partial seizure and generalized convulsion, indicating that differences in intensity ictal or postictal events cannot be reflected in the CSF cyclic nucleotide concentrations.     

Estradiol replacement to female rats facilitates dorsal hippocampal but not ventral hippocampal kindled seizure acquisition

Estradiol replacement facilitates amygdala and neocortical kindling. This study determined if estradiol also interacts with kindling of additional limbic sites, the dorsal (dH) and ventral (vH) hippocampus. During dH stimulations, ovariectomized female rats with estradiol (E) replacement required 29.7 +/- 3.5 trials to kindle and accumulated 1170 +/- 90 s of afterdischarge (AD), significantly less than the 40.6 +/- 3.7 trials and 1620 +/- 225 s in rats without estradiol (nE). E did not significantly alter the long series of partial limbic seizures preceding generalized seizures despite the early appearance of AD in the contralateral amygdala. E significantly advanced the onset of generalized seizures compared to nE (22.7 +/- 2.3 versus 27.9 +/- 3.2 trials), an event coincident with neocortical AD development. Following secondary seizure generalization, E rats rapidly completed late-kindled seizure acquisition. In contrast, nE rats required an almost twofold greater number of AD trials and AD s to complete late kindling compared to E rats. One factor in the slower late kindling of nE rats was the instability of generalized seizures which frequently regressed to focal or partial responses. In marked contrast to dH kindling, vH kindling was uneffected by E replacement. The results provide further experimental evidence for a role for estradiol in catamenial epilepsy and support our previous work suggesting that the focal origin of seizure development is critical to E facilitation of kindling and that secondary generalization of seizures is especially sensitive to estradiol.     

Relevance of kindling and related processes to human epileptogenesis

1. Kindling and related processes belong to the most extensively investigated models of experimental epilepsy. In this paper an attempt is made to outline their significance to human epileptogenesis. Below the most relevant findings are summarized: 2. Animal data: kindling and related processes are progressive in nature and occur in a great number of animal species including Rhesus monkeys and baboons; progressive epileptogenesis seems dependent on predisposition to seizure susceptibility and develops slower the higher the position of the respective species is in the phylogenetic scale; spontaneously recurrent seizures as well as permanent electroencephalographic, behavioural, electrophysiological and biochemical alterations have been observed following kindling; kindling development can be suppressed by clinically used antiepileptic drugs. These data illustrate the similarity of kindling and related processes to certain aspects of human epilepsy. 3. Human data: one case of human brain kindling and several cases of spontaneously recurrent seizures following electroconvulsive treatment are known; the progressive nature of human epilepsies is exemplified by observations of untreated patients, factors accompanying the failure of monotherapy, and the existence of multiple lesions (mirror foci) in cerebral tumour patients. 4. The material presented clearly indicates that kindling and related processes can occur in man as well as in animals. This should have implications for the treatment of epileptic patients as well as for brain stimulation techniques.     

Atipamezole, an alpha(2)-adrenoceptor antagonist, has disease modifying effects on epileptogenesis in rats

Stimulation of alpha(2)-adrenoceptors delays the development of kindling, a model of epileptogenesis in humans. Blocking alpha(2)-adrenoceptors is proconvulsant, but has beneficial effects on somatomotor recovery after experimental stroke. We investigated whether atipamezole, a selective alpha(2)-adrenoceptor antagonist, affects the recovery process from status epilepticus (SE)-induced brain damage, which affects the risk of epileptogenesis. Vehicle or atipamezole (100 microg/kg/h) treatment was started 1 week after the induction of SE and continued for 9 weeks using Alzet minipumps (n = 70). Development and severity of epilepsy, spatial and emotional learning, and histologic analysis were used as outcome measures. There were no differences in the percentage of animals with epilepsy in the different treatment groups. In the atipamezole group, however, daily seizure frequency was lower (P < 0.01), a higher percentage of epileptic animals had mild epilepsy (<1 seizure/day; P < 0.01), and seizure frequency did not increase over time compared with the vehicle group. The atipamezole group had milder hilar cell damage (P < 0.05) and less intense mossy fiber sprouting (P < 0.05). Behavioral impairments were similar between groups. Our data indicate that chronic treatment with atipamezole does not prevent epileptogenesis. There is, however, a disease-modifying effect; that is, the epilepsy that develops is milder and non-progressive. These data warrant further studies.     

Tissue plasminogen activator does not alter development of acquired epilepsy

Purpose: Tissue plasminogen activator (t‐PA), a proven therapy for acute ischemic stroke, is an endogenous serine protease associated with neuronal activity and synaptic plasticity in the brain. Its expression is enhanced after seizures, and is involved in seizure propagation throughout the brain. Therefore, the increased use of t‐PA to treat stroke may have important implications for the development of poststroke epilepsy. Using experimental and clinical approaches, we investigated the role of t‐PA in the development of epilepsy. Methods: Mice deficient in t‐PA (t‐PA^?/?) or mice transgenically modified to overexpress neuronal t‐PA (T4) underwent amygdala kindling, and seizure threshold and rates of kindling were compared to those in wild‐type mice. For the clinical study, we recruited acute ischemic stroke patients who either received intravenous t‐PA treatment on admission to hospital (n = 177; cases) or did not (n = 158; controls). We then assessed the incidence of early and late onset seizures and epilepsy in these patients. Key Findings: T4 mice were more seizure‐prone than wild‐type mice, exhibiting lower seizure thresholds (p = 0.002), but there were no significant differences observed in the rate of kindling development when comparing either T4 mice, or t‐PA^?/? mice, to their wild‐type controls. Furthermore, we found no significant differences between the proportion of poststroke patients experiencing early or late seizures, or developing epilepsy, between those who received t‐PA and those who did not. Significance: Overexpression of endogenous t‐PA lowers seizure threshold but does not influence kindling epileptogenesis. Moreover, the therapeutic administration of t‐PA in humans does not influence the development of acquired poststroke epilepsy.     

Aberrant hippocampal neurogenesis after limbic kindling: Relationship to BDNF and hippocampal-dependent memory

Seizures dramatically increase the number of adult generated neurons in the hippocampus. However, it is not known whether this effect depends on seizures that originate in specific brain regions or whether it is nonspecific to seizure activity regardless of origin. We used kindling of different brain sites to address this question. Rats received 99 kindling stimulations of the basolateral amygdala, dorsal hippocampus, or caudate nucleus over a 6-week period. After kindling, we counted the number of adult generated hippocampal neurons that were birth-dated with the proliferative marker bromodeoxyuridine (BrdU) to evaluate cell proliferation and survival under conditions of repeated seizures. Next, we counted the number of doublecortin immunoreactive (DCX-ir) cells and evaluated their dendritic complexity to determine if limbic and nonlimbic seizures have differential effects on neuronal maturation. We also quantified hippocampal brain-derived neurotrophin factor (BDNF) protein levels using an ELISA kit and assessed memory performance using a hippocampal-dependent fear conditioning paradigm. We found that limbic, but not nonlimbic, seizures dramatically increased hippocampal cell proliferation and the number of hilar-CA3 ectopic granule cells. Further, limbic kindling promoted dendritic outgrowth of DCX-ir cells and the number of DCX-ir cells containing basal dendrites. Limbic kindling also enhanced BDNF protein levels throughout the entire hippocampus and impaired the retrieval of fear memories. Collectively, our results suggest a relationship between limbic seizures, neurogenesis, BDNF protein, and cognition.     

Etiologic and Preventive Aspects of Epilepsy in the Child–Bridging the Gap Between Laboratory and Clinic

Summary: Four broad categories of basic phenomena are pertinent to developing ways to prevent epilepsy. These include mechanisms of epileptogenesis, ictal initiation and temporary entrainment by the seizure discharge of normally functioning brain, seizure propagation, and control mechanisms that function both to restrain the cascade of epileptic events culminating in a seizure and to arrest the epileptic event and restore the interictal state. In newborns and children, hypoxia-ischemia is a major factor leading to epileptogenesis, and several schemes are proposed to classify, quantify, and prevent hypoxic-ischemic encephalopathy. Control mechanisms must be better understood in order to develop prophylactic recommendations for epilepsy, and an experimental model of "kindling antagonism" may increase our understanding of these. Programs of prevention of seizures in children will evolve only if basic researchers and clinicians work productively together to develop an adequate understanding of factors important in epileptogenesis and antiepileptogenic control mechanisms.