Epileptogenesis

About: Epileptogenesis is a research topic. Over the lifetime, 4218 publications have been published within this topic receiving 170809 citations.

Dynamic changes of proteases and protease inhibitors revealed by microarray analysis in CA3 and entorhinal cortex during epileptogenesis in the rat.

Abstract: We investigated expression of genes involved in the proteolytic process during epileptogenesis in a rat model of temporal lobe epilepsy (TLE). In a previous microarray study we found prominent activation of this process, which reached highest expression during the acute and latent phase (1 week after SE) in CA3 and entorhinal cortex (EC). Detailed analysis shows differences in dynamics of the changes of several protease genes such as cathepsins, caspases, matrix metalloproteinases, and plasminogen activators. Most genes were acutely upregulated while others were mainly activated during the latent phase. Interestingly several proteolytic genes were still elevated in the chronic epileptic phase. Various protease inhibitors followed a similar time course. The identification of changes in the activation of genes involved in proteolysis at critical phases during epileptogenesis could point to potential time specific targets for intervention. The fact that several proteolytic genes were still activated in the chronic epileptic phase makes them interesting candidates to modify and slow down seizure progression.

Neurosteroids and epileptogenesis in the pilocarpine model: Evidence for a relationship between P450scc induction and length of the latent period

Abstract: The initial rate-limiting step in the biosynthesis of steroid hormones is the conversion of cholesterol to pregnenolone, which is catalyzed by cytochrome P450 side-chain cleavage enzyme (P450scc) located in the inner mitochondrial membrane. By virtue of its role in regulating the production of precursor steroid hormones, P450scc also influences the biosynthesis of reduced steroid hormone metabolites such as allopregnanolone and allotetrahydr-oxycorticosterone, which act as positive allosteric modulators of γ-aminobutyric acid (GABA)A receptors (Lambert et al., 2003). GABAA-receptor modulating neurosteroids can be synthesized in the periphery and also in the nervous system by neurons and glial cells (Jung-Testas et al., 1989; Zwain & Yen, 1999; Mellon & Griffin, 2002). It is well recognized that these steroids possess anticonvulsant properties (Rogawski & Reddy, 2004), and we recently presented evidence that they may serve as endogenous regulators of epileptogenesis (Biagini et al., 2006). Temporal lobe epilepsy with hippocampal sclerosis is the most common type of epilepsy in adults and is often characterized by the presence of an initial precipitating injury, which is then followed by recurrent seizures after a latent period of variable duration (Mathern et al., 2002). Rodents experiencing status epilepticus (SE) induced by convulsants such as pilocarpine and kainic acid or, alternatively, by repetitive stimulation of limbic structures, exhibit a disorder with similar clinical and neuropathologic features (Avoli et al., 2002). In these models, neuronal cell loss, in vulnerable brain regions such as the hippocampal CA3 area, is associated with activation of astrocytes and invasion of damaged tissue by microglial cells. In fact, intense activation of neurons as occurs during SE can induce dramatic astrocytic reactivity (Steward et al., 1991). Because neurosteroidogenic enzymes are present in astrocytes, the histopathologic changes that occur with epileptogenesis could influence neurosteroid synthesis and the availability of neurosteroids for modulation of GABAA-receptor function. In fact, in our recent study, we found that P450scc is induced in the hippocampal formation of rats following pilocarpine-induced SE (Biagini et al., 2006). This increase was detected mainly in presumptive glial cells and occurred during the latent period before the appearance of spontaneous recurrent seizures. In the present study, we extend these prior observations by showing that P450scc is induced in a diverse population of glial cells, including astrocytes, oligodendrocytes, and microglia. In addition, we have found that the extent of P450scc induction in these cells is dependent on SE duration. Finally, we confirm our previous observation that the latent period is reduced by neurosteroid synthesis inhibition with the 5α-reductase inhibitor finasteride, but only with SE of sufficient duration to induce P450scc. Taken together, our observations strengthen the view that GABAA-receptor modulating neurosteroids play a role in regulating epileptogenesis following SE.

Functionalized magnetonanoparticles for MRI diagnosis and localization in epilepsy

Abstract: The American Epilepsy Society and the National Institute of Neurological Disorders and Stroke have coauthored a list of benchmarks to be attained in the search for a cure for epilepsy (Jacobs et al., 2001), the first of which is the identification of a reliable surrogate marker of epileptogenesis and epileptogenicity. A reliable surrogate marker that can be noninvasively measured could (1) provide an inexpensive means to localize the epileptogenic region for surgical resection in patients with pharmacoresistant epilepsy who are candidates for surgery; (2) predict which patients are likely to develop epilepsy following a potentially epileptogenic brain injury, in order to institute antiepileptogenic treatment; and (3) determine which of the many therapeutic approaches, including a large number of antiepileptic drugs, vagus nerve stimulation, and deep brain stimulation, are likely to be effective in individual patients without the need to wait for another seizure to occur. One putative surrogate marker that has received recent attention is alpha methyl tryptophan (AMT), which has been used as a positron emission tomography (PET) ligand to identify epileptogenic tissues in several epilepsy conditions (Fedi et al., 2001; Duchowny, 2003; Juhasz & Chugani, 2003; Juhasz et al., 2003; Natsume et al., 2003; Juhasz et al., 2004; Kagawa et al., 2005). This proof of principle study demonstrates the use of nanotechnology to covalently attach AMT to magneto-nanoparticles (MNP) visible on magnetic resonance imaging (MRI). These particles cross the blood–brain barrier (BBB) and concentrate in epileptogenic tissues during the acute and chronic stages of an animal model of temporal lobe epilepsy, permitting their localization with standard MRI. Beyond its immediate application in epilepsy, this represents the first demonstration of a novel approach to utilize standard MRI for ligand-based functional neuroimaging, which would have the following advantages: (1) there would be no radiation risk, and thus no limit on the number of times the study could be repeated; (2) the technique could be employed in any MRI facility without need for modification; (3) tracers are relatively easy to synthesize in a short period of time; (4) they could be purchased relatively inexpensively and could be kept for prolonged periods of time without special storage requirements. This MNP-MRI approach is potentially applicable to the use of any bioactive molecules as ligands for imaging normal and abnormal cerebral function, accurately, safely, and inexpensively.

Mammalian target of rapamycin (mTOR) inhibition: potential for antiseizure, antiepileptogenic, and epileptostatic therapy.

Abstract: New epilepsy treatments are needed that not only inhibit seizures symptomatically (antiseizure) but also prevent the development of epilepsy (antiepileptogenic). The mammalian target of rapamycin (mTOR) pathway may mediate mechanisms of epileptogenesis and serve as a rational therapeutic target. mTOR inhibitors have antiepileptogenic and antiseizure effects in animal models of the genetic disease, tuberous sclerosis complex. The mTOR pathway is also implicated in epileptogenesis in animal models of acquired epilepsy and infantile spasms, although the effects of mTOR inhibitors are variable depending on the specific conditions and model. Furthermore, beneficial effects on seizures are lost when treatment is withdrawn, suggesting that mTOR inhibitors are “epileptostatic” in only stalling epilepsy progression during treatment. Clinical studies of rapamycin in human epilepsy are limited, but suggest that mTOR inhibitors at least have antiseizure effects in tuberous sclerosis patients. Further studies are needed to assess the full potential of mTOR inhibitors for epilepsy treatment.