Antiepileptogenic Potential Research Articles

Prevention or modification of epileptogenesis after brain insults: experimental approaches and translational research.

Diverse brain insults, including traumatic brain injury, stroke, infections, tumors, neurodegenerative diseases, and prolonged acute symptomatic seizures, such as complex febrile seizures or status epilepticus (SE), can induce "epileptogenesis," a process by which normal brain tissue is transformed into tissue capable of generating spontaneous recurrent seizures. Furthermore, epileptogenesis operates in cryptogenic causes of epilepsy. In view of the accumulating information about cellular and molecular mechanisms of epileptogenesis, it should be possible to intervene in this process before the onset of seizures and thereby either prevent the development of epilepsy in patients at risk or increase the potential for better long-term outcome, which constitutes a major clinical need. For identifying pharmacological interventions that prevent, interrupt or reverse the epileptogenic process in people at risk, two groups of animal models, kindling and SE-induced recurrent seizures, have been recommended as potentially useful tools. Furthermore, genetic rodent models of epileptogenesis are increasingly used in assessing antiepileptogenic treatments. Two approaches have been used in these different model categories: screening of clinically established antiepileptic drugs (AEDs) for antiepileptogenic or disease-modifying potential, and targeting the key causal mechanisms that underlie epileptogenesis. The first approach indicated that among various AEDs, topiramate, levetiracetam, carisbamate, and valproate may be the most promising. On the basis of these experimental findings, two ongoing clinical trials will address the antiepileptogenic potential of topiramate and levetiracetam in patients with traumatic brain injury, hopefully translating laboratory discoveries into successful therapies. The second approach has highlighted neurodegeneration, inflammation and up-regulation of immune responses, and neuronal hyperexcitability as potential targets for antiepileptogenesis or disease modification. This article reviews these areas of progress and discusses the challenges associated with discovery of antiepileptogenic therapies.

Ketogenic diet is antiepileptogenic in pentylenetetrazole kindled mice and decrease levels of N-acylethanolamines in hippocampus

The ketogenic diet (KD) is used for the treatment of refractory epilepsy in children, however, the mechanism(s) remains largely unknown. Also, the antiepileptogenic potential in animal models of epilepsy has been poorly addressed. Activation of cannabinoid type-1 receptor (CB 1-R) upon seizure activity may mediate neuroprotection as may several N-acylethanolamines. It is unknown how the KD interfere with the endocannabinoid system. We investigated the antiepileptogenic potential of the KD in the pentylenetetrazole kindling model in young mice and measured the hippocampal levels of CB 1-R by Western blot and of endocannabinoids and N-acylethanolamines by mass spectrometry. The KD significantly decreased incidence and severity of seizures, and significantly increased the latency to clonic convulsions. There were no changes in levels of endocannabinoids or CB 1-R expression by either seizure activity or type of diet. The level of oleoylethanolamide as well as the sum of N-acylethanolamines were significantly decreased by the KD, but were unaffected by seizure activity. The study shows that the KD had clear antiepileptogenic properties in the pentylenetetrazole kindling model and does not support a role of endocannabinoids in this model. The significance of the decreased hippocampal level of oleoylethanolamide awaits further studies.

“TOR” rents of Excitement over Rapamycin's Antiepileptogenic Potential

Response of a Neuronal Model of Tuberous Sclerosis to Mammalian Target of Rapamycin (mTOR) Inhibitors: Effects on mTORC1 and Akt Signaling Lead to Improved Survival and Function. Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H, Sahin M, Kwiatkowski DJ. J Neurosci 2008;28(21):5422–5432. Tuberous sclerosis (TSC) is a hamartoma syndrome attributable to mutations in either TSC1 or TSC2 in which brain involvement causes epilepsy, mental retardation, and autism. We have reported recently (Meikle et al., 2007) a mouse neuronal model of TSC in which Tsc1 is ablated in most neurons during cortical development. We have tested rapamycin and RAD001 [40- O-(2-hydroxyethyl)-rapamycin], both mammalian target of rapamycin mTORC1 inhibitors, as potential therapeutic agents in this model. Median survival is improved from 33 d to more than 100 d; behavior, phenotype, and weight gain are all also markedly improved. There is brain penetration of both drugs, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream target of mTORC1. In addition, there is restoration of phospho-Akt and phospho-glycogen synthase kinase 3 levels in the treated mice, consistent with restoration of Akt function. Neurofilament abnormalities, myelination, and cell enlargement are all improved by the treatment. However, dysplastic neuronal features persist, and there are only modest changes in dendritic spine density and length. Strikingly, mice treated with rapamycin or RAD001 for 23 d only (postnatal days 7–30) displayed a persistent improvement in phenotype, with median survival of 78 d. In summary, rapamycin/RAD001 are highly effective therapies for this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 and Akt signaling and, consequently, cell size and myelination. Although caution is appropriate, the results suggest the possibility that rapamycin/RAD001 may have benefit in the treatment of TSC brain disease, including infantile spasms. Rapamycin Prevents Epilepsy in a Mouse Model of Tuberous Sclerosis Complex. Zeng LH, Xu L, Gutmann DH, Wong M. Ann Neurol 2008;63(4):444–453. OBJECTIVE: Tuberous sclerosis complex (TSC) represents one of the most common genetic causes of epilepsy. TSC gene inactivation leads to hyperactivation of the mammalian target of rapamycin signaling pathway, raising the intriguing possibility that mammalian target of rapamycin inhibitors might be effective in preventing or treating epilepsy in patients with TSC. Mice with conditional inactivation of the Tsc1 gene primarily in glia ( Tsc1GFAPCKO mice) develop glial proliferation, progressive epilepsy, and premature death. Here, we tested whether rapamycin could prevent or reverse epilepsy, as well as other cellular and molecular brain abnormalities in Tsc1GFAPCKO mice. METHODS: Tsc1GFAPCKO mice and littermate control animals were treated with rapamycin or vehicle starting at postnatal day 14 (early treatment) or 6 weeks of age (late treatment), corresponding to times before and after onset of neurological abnormalities in Tsc1GFAPCKO mice. Mice were monitored for seizures by serial video-electroencephalogram and for long-term survival. Brains were examined histologically for astrogliosis and neuronal organization. Expression of phospho-S6 and other molecular markers correlating with epileptogenesis was measured by Western blotting. RESULTS: Early treatment with rapamycin prevented the development of epilepsy and premature death observed in vehicle-treated Tsc1GFAPCKO mice. Late treatment with rapamycin suppressed seizures and prolonged survival in Tsc1GFAPCKO mice that had already developed epilepsy. Correspondingly, rapamycin inhibited the abnormal activation of the mammalian target of rapamycin pathway, astrogliosis, and neuronal disorganization, and increased brain size in Tsc1GFAPCKO mice. INTERPRETATION: Rapamycin has strong efficacy for preventing seizures and prolonging survival in Tsc1GFAPCKO mice.

Antiepileptogenesis by Deep Brain Stimulation.

Low-frequency Stimulation of the Kindling Focus Delays Basolateral Amygdala Kindling in Immature Rats VelíŠek L, VelíŠkova J, Stanton PK Neurosci Lett 2002;326:61–63. Stimulation of deep brain sites is a new approach for treatment of intractable seizures. In adult rats, low-frequency stimulation (LFS; 1–3 Hz) of the kindling site interferes with the course of kindling epileptogenesis. In this study we determined whether the LFS is effective against the fast kindling in the basolateral amygdala in immature, 15-day-old rats. LFS (15 min of 1-Hz stimulation) was applied after each of the 1-s, 60-Hz kindling stimulus. LFS suppressed afterdischarge duration and seizure stage throughout the course of kindling, which indicates a strong antiepileptogenic potential. As the kindling and LFS stimulation patterns are similar to those used for induction of long-term potentiation and long-term depression (LTD), respectively, LTD or depotentiation may play a role in the mechanism of action.

Low-frequency stimulation of the kindling focus delays basolateral amygdala kindling in immature rats

Stimulation of deep brain sites is a new approach for treatment of intractable seizures. In adult rats, low-frequency stimulation (LFS; 1–3 Hz) of the kindling site interferes with the course of kindling epileptogenesis. In this study we determined whether the LFS will be effective against the fast kindling in the basolateral amygdala in immature, 15 day old rats. LFS (15 min of 1 Hz stimulation) was applied after each of the 1 s, 60 Hz kindling stimulus. LFS suppressed afterdischarge duration and seizure stage throughout the course of kindling, which indicates a strong antiepileptogenic potential. As the kindling and LFS stimulation patterns are similar to those used for induction of long-term potentiation and long-term depression (LTD), respectively, LTD or depotentiation may play a role in the mechanism of action.

Antiepileptogenic agents: how close are we?

Epilepsy is a common neurological condition, affecting about 4% of individuals over their lifetime. Epilepsy can be idiopathic, secondary to an underlying genetic abnormality or unknown causes, or acquired. Known potential causes account for about one third of epilepsy. Control of epilepsy has primarily focused on suppressing seizure activity after epilepsy has developed. An intriguing possibility is to control acquired epilepsy by preventing epileptogenesis, the process by which the brain becomes epileptic. Many laboratory models simulate human epilepsy as well as provide a system for studying epileptogenesis. The kindling model involves repeated application of subconvulsive electrical stimulation to the brain, leading to spontaneous seizures. Other models include the cortical or systemic injection of various chemicals. These models suggest that many antiepileptic drugs, from phenobarbital and valproate (valproic acid) to levetiracetam and tiagabine, have antiepileptogenic potential. Some promising other possibilities include N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists as well as the neurotrophins and their receptors. Phenobarbital, phenytoin, valproate, carbamazepine and, to a very limited extent, diazepam have been evaluated in clinical trials to test whether they actually prevent epileptogenesis in humans. Results have been very disappointing. Meta-analyses of 12 different drug-condition combinations show none with significantly lower unprovoked seizure rates among those receiving the active drug. In 4 of the 12, the observed rate was actually slightly higher among treated individuals. None of the newer drugs have been evaluated in antiepileptogenesis trials. Until some drugs demonstrate a clear antiepileptogenic effect in clinical trials, the best course to reduce the incidence of epilepsy is primary prevention of the risk-increasing events--for example, wearing helmets, using seat belts, or decreasing the risk of stroke by reducing smoking.