Citral Effects on the Expression Profile of Brain-Derived Neurotrophic Factor and Inflammatory Cytokines in Status Epilepticus-Induced Rats Using the Lithium-Pilocarpine Model.

Epilepsy is one of the most common neurological disorders. About one-third of people with epilepsy are refractory to available treatments. Studies suggest that mechanisms linked to the immune response and inflammatory process are related to seizure disorders. Citral is a monoterpene found in the essential oil of several plants, as in Cymbopogon citratus, used to make teas and has been the subject of numerous researches, from which it has been possible to demonstrate antiseizure and anti-inflammatory activities. In this study, the effects of citral on status epilepticus (SE) induced by the lithium-pilocarpine model in rats were investigated. Quantitative reverse transcription PCR (RT-qPCR) evaluated latency for seizure development, neuronal death in the hippocampus, and expression of the brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), interleukin-1ß ( IL-1ß) and factor nuclear kappa B (NF-κB) genes. The results revealed that citral was able to increase latency until the first seizure, decrease neuronal death 2 h after SE and inhibit overexpression of proinflammatory genes.

A potassium leak channel silences hyperactive neurons and ameliorates status epilepticus.

OBJECTIVE: To develop a constitutively active K(+) leak channel using TREK-1 (TWIK-related potassium channel 1; TREK-M) that is resistant to compensatory down-regulation by second messenger cascades, and to validate the ability of TREK-M to silence hyperactive neurons using cultured hippocampal neurons. To test if adenoassociated viral (AAV) delivery of TREK-M could reduce the duration of status epilepticus and reduce neuronal death induced by lithium-pilocarpine administration. METHODS: Molecular cloning techniques were used to engineer novel vectors to deliver TREK-M via plasmids, lentivirus, and AAV using a cytomegalovirus (CMV)-enhanced GABRA4 promoter. Electrophysiology was used to characterize the activity and regulation of TREK-M in human embryonic kidney (HEK-293) cells, and the ability to reduce spontaneous activity in cultured hippocampal neurons. Adult male rats were injected bilaterally with self-complementary AAV particles composed of serotype 5 capsid into the hippocampus and entorhinal cortex. Lithium-pilocarpine was used to induce status epilepticus. Seizures were monitored using continuous video-electroencephalography (EEG) monitoring. Neuronal death was measured using Fluoro-Jade C staining of paraformaldehyde-fixed brain slices. RESULTS: TREK-M inhibited neuronal firing by hyperpolarizing the resting membrane potential and decreasing input resistance. AAV delivery of TREK-M decreased the duration of status epilepticus by 50%. Concomitantly it reduced neuronal death in areas targeted by the AAV injection. SIGNIFICANCE: These findings demonstrate that TREK-M can silence hyperexcitable neurons in the brain of epileptic rats and treat acute seizures. This study paves the way for an alternative gene therapy treatment of status epilepticus, and provides the rationale for studies of AAV-TREK-M's effect on spontaneous seizures in chronic models of temporal lobe epilepsy.

Frontal motor seizure following non-convulsive status epilepticus in ring chromosome 20 syndrome.

The ring chromosome 20 syndrome is a rare syndrome characterized by intractable epilepsy with particular electro clinical features including episodes of prolonged confusional state and nocturnal frontal lobe seizures. We report a 17-year-old girl who had intractable epilepsy with frontal seizure and prolonged confusional state secondary to non-convulsive status epilepticus. The diagnosis of ring chromosome 20 was suspected and confirmed by karyotype. The cytogenetic study of CHRNA4 and KCNQ2 genes did not detect deletion in the ring chromosome 20. During video-EEG recording, this girl presented a non-convulsive status epilepticus that lasted more than 20 minutes followed by typical frontal lobe seizure. This association was not previously described, and was probably caused by chromosomal instability.

Vitamins, not surgery: spinal fluid testing in hemispheric epilepsy.

Metabolic testing in spinal fluid is not routinely obtained in every patient with refractory epilepsy or status epilepticus. A 9-month-old girl who was referred for surgical treatment of refractory status epilepticus suggestive of a right hemispheric focus; cranial magnetic resonance imaging was unremarkable. The patient received a metabolic evaluation according to institutional protocol and was noted to have a spinal fluid peak characteristically seen in folinic acid-responsive epilepsy. Subsequent testing revealed a deleterious mutation in the ALDH7A1 gene. At last follow-up, the patient was seizure free on folinic acid and pyridoxal 5'-phosphate supplementation. Surgery was not performed. Metabolic testing in spinal fluid is strongly urged in all patients with refractory epilepsy or status epilepticus when an underlying etiology is not known.

Histone modifications in status epilepticus induced by kainate.

Animal models of epilepsy have allowed the determination of the basic molecular and cellular mechanisms of epileptogenesis. Generalized limbic seizures and subsequent status epilepticus can be induced by either pilocarpine, the muscarinic acetylcholine receptor agonist or kainate, the glutamate receptor agonist. There has been increasing interest that chromatin remodeling might play a critical role in gene regulation even in non-dividing cells such as neurons. One form of chromatin remodeling is histone amino-terminal modification that can generate synergistic or antagonistic affinities for the interactions of transcriptional factors, in turn causing changes in gene activity. Two widely studied histone modification processes are histone acetylation and phosphorylation. While histone hyperacetylation indicates an increase in gene activity, its hypoacetylation marks gene repression. Both states are controlled by a dynamic interplay of histone acetyltransferase (HAT) and histone deacetylase (HDAC). We have found the upregulation of acetylation and phosphorylation of histones, coupled with status epilepticus after kainate administration. c-fos and c-jun mRNA have been sequentially induced in response to kainate, in different hippocampal subpopulations starting from the dentate gyrus and spreading to the cornus ammonis regions well correlated with the spatio-temporal distribution of histone H4 hyperacetylation. Both histone modifications are associated with the c-fos gene promoter after kainate stimulation, while only histone acetylation with the c-jun gene. Pretreatment with curcumin, which has a HAT inhibitory activity specific for CBP/p300, attenuates histone modifications, IEGs expression and also the severity of status epilepticus after kainate treatment. Histone modifications may have a crucial role in the development of epilepsy induced by kainate.