Endocrine abnormalities in human temporal lobe epilepsy

Patients with temporal lobe epilepsy secrete ACTH at higher rates and in greater amounts than normal subjects. Temporal lobectomy restores ACTH secretion to normal amounts and rates. The ACTH secretion in temporal lobe epilepsy is independent of anticonvulsant drug effect and seizure frequency. Electrical stimulation of medial temporal lobe structures in patients with temporal lobe epilepsy affected ACTH secretion in a manner consistent with the hypothesis that ACTH secretion is regulated by tonic inhibition. A defect in the excitatory and/or inhibitory components of this regulatory process appears to exist in temporal lobe epilepsy.     

Laboratory animal models of temporal lobe epilepsy

Temporal lobe epilepsy is a common human disease that is difficult to treat. The pathogenesis of temporal lobe epilepsy, which holds many unresolved questions, and opportunities for creating more effective treatments and preventative strategies are reviewed herein. Laboratory animal models are essential to meet these challenges. How models are created, how they compare with each other and with the disease in human patients, and how they advance our understanding of temporal lobe epilepsy are described.     

海马中的内源性爆发式放电神经元与颞叶癫痫

颞叶癫痫(temporal lobe epilepsy,TLE)是常见的难治性癫痫,主要累及到海马及海马旁结构等边缘网络。爆发式放电神经元(bursting—firing neurons,BFNs)的活动是促使海马结构产生癫痫电活动及相关病理性改变的重要因素之一。BFNs是一类能够由刺激引起、甚至自发产生成串高频爆发式放电(bursting)的神经元。爆发式放电增加了突触传递的效率,促使突触活动产生短时程和长时程可塑性变化,募集邻近神经元产生同步化放电。BFNs的电活动在癫痫相关性电活动中可能具有起搏点的作用。同时,癫痫电活动也促使内源性BFNs的改变,以及调制非爆发式放电神经元向BFNs的转变,导致海马结构内癫痫电活动的进展和扩散,最终促使癫痫相关性病理性改变和脑的高级功能的损害。     

Altered Kir and gap junction channels in temporal lobe epilepsy

Since astrocytes may sense and respond to neuronal activity these cells are now considered important players in brain signaling. Astrocytes form large gap junction coupled syncytia allowing them to clear the extracellular space from K⁺ and neurotransmitters accumulating during neuronal activity, and redistribute it to sites of lower extracellular concentrations. Increasing evidence suggests a crucial role for dysfunctional astrocytes in the etiology of epilepsy. Notably, alterations in expression, localization and function of astroglial K⁺ channels as well as impaired K⁺ buffering was observed in specimens from patients with pharmacoresistant temporal lobe epilepsy and in chronic epilepsy models. Altered astroglial gap junction coupling has also been reported in epileptic tissue which, however, seems to play a dual role: (i) junctional coupling counteracts hyperactivity by facilitating clearance of elevated extracellular K⁺ and glutamate while (ii) it also provides a pathway for energetic substrates and fuels neuronal activity. Dysfunctional astrocytes should be considered promising targets for new therapeutic strategies.     

Immunoproteasome expression is induced in mesial temporal lobe epilepsy

Immunoproteasome has been associated to neurodegenerative and autoimmune diseases as a marker and regulator of inflammatory mechanisms. Its expression in the brain may occur upon neuroinflammation in different cell types and affect a variety of homeostatic and inflammatory pathways including the oxidized protein clearance and the self-antigen presentation. In the present study we investigated the immunoproteasome expression in hippocampi and cortex of patients affected by different histopathological forms of pharmaco-resistent mesial temporal lobe epilepsy. We identified a pathology-specific pattern of immunoproteasome expression, which could provide insight into the complex neuroinflammatory pathogenic components of this disease.     

Developing a new animal model of temporal lobe epilepsy

Epilepsy affects 1-2 % of the population. For 30 % of these patients, their syndrome will be refractory to medical treatment. To improve our understanding and treatment of the epilepsies, we need to develop clinically relevant animal models. As temporal lobe epilepsy is often preceded by prolonged febrile seizures and in our population associated with a focal cortical dysplasia, we hypothesised that an underlying predisposing anatomical lesion would predispose individuals to develop prolonged febrile seizures and that temporal lobe epilepsy would later develop. As predicted, all the lesioned animals developed prolonged febrile seizures, while all other control groups only showed simple febrile seizures. After a latent period, 86 % of the animals who had experienced a prolonged seizure developed spontaneously recurrent limbic seizures. We now need to understand the anatomical and electrophysiological changes underlying this new epilepsy model to try and develop more effective treatments for the condition.     

Ganglioside changes associated with temporal lobe epilepsy in the human hippocampus

To understand better the molecular and cellular events associated with status epilepticus, a multifaceted analysis has begun on hippocampal tissues therapeutically removed from patients with temporal lobe epilepsy. In this first study, quantitative changes in major ganglioside species are reported, as well as the immunocytochemical localization on the ganglioside GD3 in epileptic human hippocampus. Although significant variations were found between patients, the pattern of change was consistent when compared to normal values obtained from an autopsied specimen and the literature. Total ganglioside content was reduced in epileptic hippocampi, which was attributable, in part, to pyramidal cell loss found in CA1 and CA3. In each case, the percentage of ganglioside GD3 was increased significantly, while ganglioside GD1a decreased. The former change is probably associated with reactive astrocytosis and the latter with loss of neuronal dendrites. Immunocytochemical localization revealed GD3 in the stratum radiatum and the subgranular layer of the dentate gyrus. In these areas, GD3 was present in punctate structures and astrocytes. These findings indicate that GD3 increases in selected areas of the sclerotic hippocampus and is presumably related to localized accumulation of reactive glial cells. Since gangliosides have a high affinity for calcium and localized increase in extracellular calcium could disrupt normal neuronal function, the localized increase in GD3 may not only denote reactive glial cells but may contribute directly to the altered, hyperexcitable condition of epilepsy.