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.

Caloric Restriction and Ketogenic Diet Therapy for Epilepsy: A Molecular Approach Involving Wnt Pathway and KATP Channels.

Epilepsy is a neurological disorder in which, in many cases, there is poor pharmacological control of seizures. Nevertheless, it may respond beneficially to alternative treatments such as dietary therapy, like the ketogenic diet or caloric restriction. One of the mechanisms of these diets is to produce a hyperpolarization mediated by the adenosine triphosphate (ATP)-sensitive potassium (KATP) channels (KATP channels). An extracellular increase of K+ prevents the release of Ca2+ by inhibiting the signaling of the Wnt pathway and the translocation of ß-catenin to the cell nucleus. Wnt ligands hyperpolarize the cells by activating K+ current by Ca2+. Each of the diets described in this paper has in common a lower use of carbohydrates, which leads to biochemical, genetic processes presumed to be involved in the reduction of epileptic seizures. Currently, there is not much information about the genetic processes implicated as well as the possible beneficial effects of diet therapy on epilepsy. In this review, we aim to describe some of the possible genes involved in Wnt pathways, their regulation through the KATP channels which are implicated in each one of the diets, and how they can reduce epileptic seizures at the molecular level.

Commentary: Participation of Sox-1 Expression and Signaling of ß-Catenin in the Pathophysiology of Generalized Seizures in Cerebellum of Rat.

Epilepsy is one of the most common neurological disorders in humans, and the role of cerebellum in its physiopathology remains the subject of study. Bergmann glia in the cerebellar cortex regulates the homeostasis of Purkinje cells, the axons of which target the dentate and interpositus nuclei, which form the main cerebellar output to other structures in the central nervous system involved in Epilepsy. Sox-1 is a transcription factor expressed in Bergmann glia and its binding to ß-Catenin further inhibits the Wnt pathway. ß-Catenin is widely expressed in cerebellum. It has been reported that ß-Catenin signaling is increased as the hippocampus receives repeated electrical stimuli and this is related with apoptosis of neurons. In the cerebellum, the recurrence of seizures results in Purkinje cells death, although the mechanisms remain unclear.