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Epileptogenesis

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


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Journal ArticleDOI
TL;DR: Increased blood–brain barrier permeability is radiologically detectable in regions affected by drug‐resistant epileptogenic lesions and the hypothesis that lipophilic and hydrophilic drug distribution is differentially affected by BBB damage is tested.
Abstract: The blood–brain barrier (BBB) protects the brain from harmful substances in the bloodstream, while supplying the brain with the nutrients required for proper function. The endothelial cell cerebrovasculature lining also regulates brain penetration of drugs. Because of the presence of such complex and yet delicate mechanisms of vascular protection, pharmacologic targeting of central nervous system (CNS) pathologies was and remains a challenge. In general, it is assumed that breaching the BBB will improve CNS drug delivery (Kroll & Neuwelt, 1998), but altered BBB function associated with CNS pathologies such as epilepsy is also a characteristic of pharmacokinetic drug resistance (Oby & Janigro, 2006). Therefore, the interplay between BBB function or failure, and drug delivery is more complex than originally believed. Is there a link between leakage of the BBB, seizure-epileptic pathology, and multiple drug resistance? Several evidences have shown BBB damage and profound remodeling of the cerebrovasculature during or immediately after seizures (Marchi et al., 2006, 2007b). This has been interpreted as a vascular consequence of spontaneous seizures. It has also been repeatedly shown that BBB leakage is sufficient to promote seizures (Oby & Janigro, 2006; Marchi et al., 2007a,b; Uva et al., 2007) or epileptogenesis (Seiffert et al., 2004; van Vliet et al., 2007). Whatever the temporal or causal relationship between BBB leakage and seizures, it is clear that the epileptic brain is characterized by an abnormal blood–brain interface. The integrity of the BBB is clinically evaluated with magnetic resonance imaging (MRI) techniques. Although T1-contrast enhancement (Gd++) is a reliable imaging method for direct testing of BBB permeability, structural changes at a cellular level and changes of the distribution of water between the extra- and intracellular compartments can be assessed by diffusion-weighted imaging (DWI) and by calculating the extent of passive water motion or diffusivity (apparent diffusion coefficient, ADC). Periictal and postictal human studies using DWI or diffusion tensor imaging (DTI) showed, in some cases, transiently decreased local diffusivity, potentially in concordance with the epileptic zone (Vincent et al., 1995; Flink & Atchison, 2003; Lang & Vincent, 2003; Vernino, 2007). Diffusion studies have also demonstrated areas of significantly increased diffusivity in patients with partial epilepsies during the interictal period (Diehl et al., 1999, 2001; Hufnagel et al., 2003; Diehl et al., 2005). These results suggest that abnormal cerebrovascular and parenchymal homeostatic mechanisms are altered in epileptics. In human epilepsy, overexpression of drug-resistance efflux proteins at the BBB has been studied extensively in the framework of antiepileptic drug (AED) refractoriness, but additional mechanisms have also been proposed (Loscher & Potschka, 2005; Oby & Janigro, 2006). Given that the pathology of drug-resistant epilepsy often reveals morphologic and functional abnormalities of the BBB, protein extravasation, and brain edema, it is reasonable to hypothesize that the physical–chemical properties of AEDs will differently predict CNS drug delivery to the epileptic focus. For example, most AEDs are highly lipid soluble and tightly protein bound, and their permeability across an intact BBB is controlled by parameters. It is possible that altered brain water content or protein extravasation combined with overexpression of drug transporters may affect the distribution of AEDs. We have focused our study on the consequences of BBB damage on serum protein extravasation and brain water content. Because this was induced acutely and by iatrogenic means, the results may bear specific relevance for sudden episodes of BBB disruption (BBBD), as seen in traumatic brain injury (Schmidt & Grady, 1993; Korn et al., 2005; Tomkins et al., 2008). For this pilot study we used the hydrophilic radiolabel compounds 3H-deoxy-glucose (DOG) and 3H-sucrose (SUC) and the lipophilic AEDs 14C-phenytoin (PHT) and 14C-diazepam (DIA).

76 citations

Journal ArticleDOI
TL;DR: The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models and facilitate the identification of age‐specific, syndrome‐ or etiology‐specific therapies for the epilepsies and attendant comorbridities, including the drug‐resistant forms.
Abstract: Animal models have provided a wealth of information on mechanisms of epileptogenesis and comorbidogenesis, and have significantly advanced our ability to investigate the potential of new therapies. Processes implicating brain inflammation have been increasingly observed in epilepsy research. Herein we discuss the progress on animal models of epilepsy and comorbidities that inform us on the potential role of inflammation in epileptogenesis and comorbidity pathogenesis in rodent models of West syndrome and the Theiler's murine encephalomyelitis virus (TMEV) mouse model of viral encephalitis-induced epilepsy. Rat models of infantile spasms were generated in rat pups after right intracerebral injections of proinflammatory compounds (lipopolysaccharides with or without doxorubicin, or cytokines) and were longitudinally monitored for epileptic spasms and neurodevelopmental and cognitive deficits. Anti-inflammatory treatments were tested after the onset of spasms. The TMEV mouse model was induced with intracerebral administration of TMEV and prospective monitoring for handling-induced seizures or seizure susceptibility, as well as long-term evaluations of behavioral comorbidities of epilepsy. Inflammatory processes are evident in both models and are implicated in the pathogenesis of the observed seizures and comorbidities. A common feature of these models, based on the data so far available, is their pharmacoresistant profile. The presented data support the role of inflammatory pathways in epileptogenesis and comorbidities in two distinct epilepsy models. Pharmacoresistance is a common feature of both inflammation-based models. Utilization of these models may facilitate the identification of age-specific, syndrome- or etiology-specific therapies for the epilepsies and attendant comorbidities, including the drug-resistant forms.

76 citations

Journal ArticleDOI
TL;DR: It is demonstrated that pharmacological removal of reactive oxygen species (ROS) prevents 1) oxidative stress, 2) deficits in mitochondrial oxygen consumption rates, 3) hippocampal neuronal loss and 4) cognitive dysfunction without altering the intensity of the initial status epilepticus or epilepsy development in a rat model of SE-induced TLE.

76 citations

Journal ArticleDOI
TL;DR: Despite a temporal reduction in seizure frequency with SC/PHT treatment, SC does not seem to be a suitable approach for anti-epileptogenic or anti-EPileptic therapy.

76 citations

Journal ArticleDOI
TL;DR: This study explored the effect on the central nervous systems of freely moving adult rats, of repeated brief epileptic seizures induced by systemic injection of pentylenetetrazole, a GABA-A receptor antagonist, and found that neurogenesis is not a secondary consequence of neuronal cell death, but rather an independent effect of recurrent epilepsyptic seizures.

76 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
2023181
2022348
2021245
2020219
2019210
2018209