Accurate Neurosurgery for the Establishment of the Electric Kindling Model of Epilepsy in Mice.

This article describes in detail the essential stereotaxic neurosurgery to develop the electric experimental kindling model in mice. To date, available literature describing the methodology of the kindling model is very poor and usually neglects many relevant details about the neurosurgery, such as the manufacture of the electrodes, accurate stereotaxic coordinates of the amygdala nuclei, and the general surgery procedures (e.g., anesthesia, postsurgical recovery, fit survival of the animal's). The electric kindling model produces a progressive development of generalized tonic-clonic seizures, which can be assessed by electroencephalography and behavioral responses. The seizures displayed are produced by a repeated low-intensity electrical stimulation in specific regions of the brain that is achieved through the previous implantation of electrodes. In this study, the aim was to implant the electrodes in basolateral amygdaloid nucleus (BLA). In order to successfully establish the kindling experimental model, neurosurgery to place the electrodes is an essential step to develop the epileptogenic phenomenon. It crucial that the surgery is carried out with exceptional exactitude, because in that way the experimental model represents an accurate and valid tool to study and understand epilepsy and the results obtained can be used to develop further strategies in epilepsy clinical research.

Apoptosis in the Dentate Nucleus Following Kindling-induced Seizures in Rats.

BACKGROUND: Epilepsy is a common neurological disorder characterized by abnormal and recurrent neuronal discharges that result in epileptic seizures. The dentate nuclei of the cerebellum receive excitatory input from different brain regions. Purkinje cell loss due to chronic seizures could lead to decreased inhibition of these excitatory neurons, resulting in the activation of apoptotic cascades in the dentate nucleus. OBJECTIVE: The present study was designed to determine whether there is a presence of apoptosis (either intrinsic or extrinsic) in the dentate nucleus, the final relay of the cerebellar circuit, following kindling-induced seizures. METHODS: In order to determine this, seizures were triggered via the amygdaloid kindling model. Following 0, 15, or 45 stimuli, rats were sacrificed, and the cerebellum was extracted. It was posteriorly prepared for the immunohistochemical analysis with cell death biomarkers: TUNEL, Bcl-2, truncated Bid (tBid), Bax, cytochrome C, and cleaved caspase 3 (active form). Our findings reproduce results obtained in other parts of the cerebellum. RESULTS: We found a decrease of Bcl-2 expression, an anti-apoptotic protein, in the dentate nucleus of kindled rats. We also determined the presence of TUNEL-positive neurons, which confirms the presence of apoptosis in the dentate nucleus. We observed the expression of tBid, Bax, as well as cytochrome C and cleaved caspase-3, the main executor caspase of apoptosis. CONCLUSION: There is a clear activation of both the intrinsic and extrinsic apoptotic pathways in the cells of the dentate nucleus of the cerebellum of rats subjected to amygdaloid kindling.

Antiepileptogenic Effect of Retinoic Acid.

Retinoic acid, a metabolite of vitamin A, acts through either genomic or nongenomic actions. The genomic action of retinoids exerts effects on gene transcription through interaction with retinoid receptors such as retinoic acid receptors (RARα, ß, and γ) and retinoid X receptors (RXRα, ß, and γ) that are primarily concentrated in the amygdala, pre-frontal cortex, and hippocampal areas in the brain. In response to retinoid binding, RAR/RXR heterodimers undergo major conformational changes and orchestrate the transcription of specific gene networks. Previous experimental studies have reported that retinoic acid exerts an antiepileptogenic effect through diverse mechanisms, including the modulation of gap junctions, neurotransmitters, long-term potentiation, calcium channels and some genes. To our knowledge, there are no previous or current clinical trials evaluating the use of retinoic acid for seizure control.

Neuronal Excitability in Epileptogenic Zones Regulated by the Wnt/ Β-Catenin Pathway.

Epilepsy is a neurological disorder that involves abnormal and recurrent neuronal discharges, producing epileptic seizures. Recently, it has been proposed that the Wnt signaling pathway is essential for the central nervous system development and function because it modulates important processes such as hippocampal neurogenesis, synaptic clefting, and mitochondrial regulation. Wnt/ß- catenin signaling regulates changes induced by epileptic seizures, including neuronal death. Several genetic studies associate Wnt/ß-catenin signaling with neuronal excitability and epileptic activity. Mutations and chromosomal defects underlying syndromic or inherited epileptic seizures have been identified. However, genetic factors underlying the susceptibility of an individual to develop epileptic seizures have not been fully studied yet. In this review, we describe the genes involved in neuronal excitability in epileptogenic zones dependent on the Wnt/ß-catenin pathway.