Showing papers on "Epileptogenesis published in 2021"

The Kainic acid models of Temporal Lobe Epilepsy

Abstract: Experimental models of epilepsy are useful to identify potential mechanisms of epileptogenesis, seizure genesis, comorbidities, and treatment efficacy. The kainic acid (KA) model is one of the most commonly used. Several modes of administration of KA exist, each producing different effects in a strain-, species-, gender-, and age-dependent manner. In this review, we discuss the advantages and limitations of the various forms of KA administration (systemic, intrahippocampal, and intranasal), as well as the histologic, electrophysiological, and behavioral outcomes in different strains and species. We attempt a personal perspective and discuss areas where work is needed. The diversity of KA models and their outcomes offers researchers a rich palette of phenotypes, which may be relevant to specific traits found in patients with temporal lobe epilepsy.

Aquaporin-4 Reduces Post-Traumatic Seizure Susceptibility by Promoting Astrocytic Glial Scar Formation in Mice.

Abstract: Seizures are important neurologic complications following traumatic brain injury (TBI) and are reported for up to 50% of patients with TBI. Despite several studies, no drug strategy has been able to alter the biological events leading to epileptogenesis. The glial water channel aquaporin-4 (AQP4) was shown to facilitate cytotoxic cell swelling in ischemia and glial scar formation following stab wound injury. In this study, we examined post-traumatic seizure susceptibility of AQP4-deficient mice (AQP4-/-) after injection of pentylenetetrazole (PTZ) 1 month after controlled cortical impact (CCI) and compared them to wild-type sham injury controls. After PTZ injection, AQP4-/- mice demonstrated dramatically shortened seizure latency (120 ± 40 seconds vs. 300 ± 70 seconds, p < 0.001) and increased seizure severity (grade 7.5 ± 0.4 vs. 5.8 ± 0.4, p < 0.001) compared to their wild-type counterparts. Morphometric analysis demonstrated a significant two-fold reduction in astrocytosis with concomitant increase in ...

Brain concentrations of glutamate and GABA in human epilepsy: A review.

Abstract: An imbalance between excitation and inhibition has been a longstanding proposed mechanism regarding ictogenesis and epileptogenesis. This imbalance is related to increased extracellular glutamate in the brain and/or reduction in GABA concentrations, leading to excitotoxicity, seizures, and cell death. This review aims to summarize the microdialysis and magnetic resonance spectroscopy (MRS) literature investigating glutamate and GABA concentrations in epilepsy patients, present limitations, and suggest future directions to help direct the search for novel epilepsy treatments. The majority of microdialysis studies demonstrated increased glutamate in epileptic regions either compared to control regions or to baseline levels; however, sample sizes were small, with some statistical comparisons missing. For the MRS research, two of six studies reported significant changes in glutamate levels compared to controls, though the results were mixed, with one reporting increased and the other reporting decreased glutamate levels. Eleven of 20 studies reported significant changes in Glx (glutamate + glutamine) or Glx ratios, with most reporting increased levels, except for a few epilepsy syndromes where reduced levels were reported. Few studies investigated GABA concentrations, with one microdialysis and four spectroscopy studies reporting increased GABA levels, and one study reporting decreased GABA in a different brain region. Based on this review, future research should account for medication use; include measurements of GABA, glutamate, and glutamine; use high-tesla strength MRI; and further evaluate the timing of microdialysis. Understanding the importance of brain glutamate and GABA levels in epilepsy may provide direction for future therapies and treatments.

Inflammation, ictogenesis, and epileptogenesis: An exploration through human disease

Abstract: Epilepsy is seen historically as a disease of aberrant neuronal signaling manifesting as seizures. With the discovery of numerous auto-antibodies and the subsequent growth in understanding of autoimmune encephalitis, there has been an increasing emphasis on the contribution of the innate and adaptive immune system to ictogenesis and epileptogenesis. Pathogenic antibodies, complement activation, CD8+ cytotoxic T cells, and microglial activation are seen, to various degrees, in different seizure-associated neuroinflammatory and autoimmune conditions. These aberrant immune responses are thought to cause disruptions in neuronal signaling, generation of acute symptomatic seizures, and, in some cases, the development of long-term autoimmune epilepsy. Although early treatment with immunomodulatory therapies improves outcomes in autoimmune encephalitides and autoimmune epilepsies, patient identification and treatment selection are not always clear-cut. This review examines the role of the different components of the immune system in various forms of seizure disorders including autoimmune encephalitis, autoimmune epilepsy, Rasmussen encephalitis, febrile infection-related epilepsy syndrome (FIRES), and new-onset refractory status epilepticus (NORSE). In particular, the pathophysiology and unique cytokine profiles seen in these disorders and their links with diagnosis, prognosis, and treatment decision-making are discussed.

A critical period of neuronal activity results in aberrant neurogenesis rewiring hippocampal circuitry in a mouse model of epilepsy.

Abstract: In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice. Adult-born granule cells integrate in hippocampal circuitry and contribute to hippocampal function. Here, the authors show that a critical period of neuronal activity regulates aberrant neurogenesis to rewire hippocampal circuitry and drive seizures in a mouse model of epilepsy.

Seizures and Epilepsy After Stroke: Epidemiology, Biomarkers and Management

Abstract: Stroke is the leading cause of seizures and epilepsy in older adults. Patients who have larger and more severe strokes involving the cortex, are younger, and have acute symptomatic seizures and intracerebral haemorrhage are at highest risk of developing post-stroke epilepsy. Prognostic models, including the SeLECT and CAVE scores, help gauge the risk of epileptogenesis. Early electroencephalogram and blood-based biomarkers can provide information additional to the clinical risk factors of post-stroke epilepsy. The management of acute versus remote symptomatic seizures after stroke is markedly different. The choice of an ideal antiseizure medication should not only rely on efficacy but also consider adverse effects, altered pharmacodynamics in older adults, and the influence on the underlying vascular co-morbidity. Drug-drug interactions, particularly those between antiseizure medications and anticoagulants or antiplatelets, also influence treatment decisions. In this review, we describe the epidemiology, risk factors, biomarkers, and management of seizures after an ischaemic or haemorrhagic stroke. We discuss the special considerations required for the treatment of post-stroke epilepsy due to the age, co-morbidities, co-medication, and vulnerability of stroke survivors.

Neocortical development and epilepsy: insights from focal cortical dysplasia and brain tumours

Abstract: During the past decade, there have been considerable advances in understanding of the genetic and morphogenic processes underlying cortical malformations and developmental brain tumours. Focal malformations are caused by somatic (postzygotic) variants in genes related to cell growth (ie, in the mTOR pathway in focal cortical dysplasia type 2), which are acquired in neuronal progenitors during neurodevelopment. In comparison, developmental brain tumours result from somatic variants in genes related to cell proliferation (eg, in the MAP-kinase pathway in ganglioglioma), which affect proliferating glioneuronal precursors. The timing of the genetic event and the specific gene involved during neurodevelopment will drive the nature and size of the lesion, whether it is a developmental malformation or a brain tumour. There is also emerging evidence that epigenetic processes underlie a molecular memory in epileptogenesis. This knowledge will together facilitate understanding of why and how patients with these lesions have epilepsy, and could form a basis for a move towards precision medicine for this challenging cohort of patients.

Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus

Abstract: Extensive activation of glial cells during a latent period has been well documented in various animal models of epilepsy. However, it remains unclear whether activated glial cells contribute to epileptogenesis, i.e., the chronically persistent process leading to epilepsy. Particularly, it is not clear whether interglial communication between different types of glial cells contributes to epileptogenesis, because past literature has mainly focused on one type of glial cell. Here, we show that temporally distinct activation profiles of microglia and astrocytes collaboratively contributed to epileptogenesis in a drug-induced status epilepticus model. We found that reactive microglia appeared first, followed by reactive astrocytes and increased susceptibility to seizures. Reactive astrocytes exhibited larger Ca2+ signals mediated by IP3R2, whereas deletion of this type of Ca2+ signaling reduced seizure susceptibility after status epilepticus. Immediate, but not late, pharmacological inhibition of microglial activation prevented subsequent reactive astrocytes, aberrant astrocyte Ca2+ signaling, and the enhanced seizure susceptibility. These findings indicate that the sequential activation of glial cells constituted a cause of epileptogenesis after status epilepticus. Thus, our findings suggest that the therapeutic target to prevent epilepsy after status epilepticus should be shifted from microglia (early phase) to astrocytes (late phase).

Modulation of Glucose Availability and Effects of Hypo- and Hyperglycemia on Status Epilepticus: What We Do Not Know Yet?

Abstract: Status epilepticus (SE) can lead to serious neuronal damage and act as an initial trigger for epileptogenic processes that may lead to temporal lobe epilepsy (TLE). Besides promoting neurodegeneration, neuroinflammation, and abnormal neurogenesis, SE can generate an extensive hypometabolism in several brain areas and, consequently, reduce intracellular energy supply, such as adenosine triphosphate (ATP) molecules. Although some antiepileptic drugs show efficiency to terminate or reduce epileptic seizures, approximately 30% of TLE patients are refractory to regular antiepileptic drugs (AEDs). Modulation of glucose availability may provide a novel and robust alternative for treating seizures and neuronal damage that occurs during epileptogenesis; however, more detailed information remains unknown, especially under hypo- and hyperglycemic conditions. Here, we review several pathways of glucose metabolism activated during and after SE, as well as the effects of hypo- and hyperglycemia in the generation of self-sustained limbic seizures. Furthermore, this study suggests the control of glucose availability as a potential therapeutic tool for SE.

The matrix metalloproteinase inhibitor IPR-179 has antiseizure and antiepileptogenic effects

Abstract: Matrix metalloproteinases (MMPs) are synthesized by neurons and glia and released into the extracellular space, where they act as modulators of neuroplasticity and neuroinflammatory agents. Development of epilepsy (epileptogenesis) is associated with increased expression of MMPs, and therefore, they may represent potential therapeutic drug targets. Using quantitative PCR (qPCR) and immunohistochemistry, we studied the expression of MMPs and their endogenous inhibitors tissue inhibitors of metalloproteinases (TIMPs) in patients with status epilepticus (SE) or temporal lobe epilepsy (TLE) and in a rat TLE model. Furthermore, we tested the MMP2/9 inhibitor IPR-179 in the rapid-kindling rat model and in the intrahippocampal kainic acid mouse model. In both human and experimental epilepsy, MMP and TIMP expression were persistently dysregulated in the hippocampus compared with in controls. IPR-179 treatment reduced seizure severity in the rapid-kindling model and reduced the number of spontaneous seizures in the kainic acid model (during and up to 7 weeks after delivery) without side effects while improving cognitive behavior. Moreover, our data suggest that IPR-179 prevented an MMP2/9-dependent switch-off normally restraining network excitability during the activity period. Since increased MMP expression is a prominent hallmark of the human epileptogenic brain and the MMP inhibitor IPR-179 exhibits antiseizure and antiepileptogenic effects in rodent epilepsy models and attenuates seizure-induced cognitive decline, it deserves further investigation in clinical trials.

Seizures in the neonate: A review of etiologies and outcomes

Abstract: Neonatal seizures occur in their majority in close temporal relation to an acute brain injury or systemic insult, and are accordingly defined as acute symptomatic or provoked seizures. However less frequently, unprovoked seizures may also present in the neonatal period as secondary to structural brain abnormalities, thus corresponding to structural epilepsies, or to genetic conditions, thus corresponding to genetic epilepsies. Unprovoked neonatal seizures should be thus considered as the clinical manifestation of early onset structural or genetic epilepsies that often have the characteristics of early onset epileptic encephalopathies. In this review, we address the conundrum of neonatal seizures including acute symptomatic, remote symptomatic, provoked, and unprovoked seizures, evolving to post-neonatal epilepsies, and neonatal onset epilepsies. The different clinical scenarios involving neonatal seizures, each with their distinct post-neonatal evolution are presented. The structural and functional impact of neonatal seizures on brain development and the concept of secondary epileptogenesis, with or without a following latent period after the acute seizures, are addressed. Finally, we underline the need for an early differential diagnosis between an acute symptomatic seizure and an unprovoked seizure, since it is associated with fundamental differences in clinical evolution. These are crucial aspects for neonatal management, counselling and prognostication. In view of the above aspects, we provide an outlook on future strategies and potential lines of research in this field.

PTZ kindling model for epileptogenesis, refractory epilepsy, and associated comorbidities: relevance and reliability

Abstract: Pentylenetetrazole (PTZ)-induced seizure is one of the gold standard mouse models for rapid evaluation of novel anticonvulsants. Synchronically, PTZ induced kindling in mice is also a simple and well accepted model of chronic epilepsy. PTZ kindling has been explored for studying epileptogenesis, epilepsy-associated comorbidities, and refractory epilepsy. This review summarizes the potential of PTZ kindling in mice and its modifications for its face, construct, and predictive validity to screen antiepileptogenic drugs, combined or add on novel and safe therapies for treatment of epilepsy-associated depression and cognitive impairment as well as effective interventions for pharmacoresistant epilepsy.

Exacerbation of Epilepsy by Astrocyte Alkalization and Gap Junction Uncoupling.

Abstract: Seizures invite seizures. At the initial stage of epilepsy, seizures intensify with each episode; however, the mechanisms underlying this exacerbation remain to be solved. Astrocytes have a strong control over neuronal excitability and the mode of information processing. This control is accomplished by adjusting the levels of various ions in the extracellular space. The network of astrocytes connected via gap junctions allows a wider or more confined distribution of these ions depending on the open probability of the gap junctions. K+ clearance relies on the K+ uptake by astrocytes and the subsequent diffusion of K+ through the astrocyte network. When astrocytes become uncoupled, K+ clearance becomes hindered. Accumulation of extracellular K+ leads to hyperexcitability of neurons. Here, using acute hippocampal slices from mice, we uncovered that brief periods of epileptiform activity result in gap junction uncoupling. In slices that experienced short-term epileptiform activity, extracellular K+ transients in response to glutamate became prolonged. Na+ imaging with a fluorescent indicator indicated that intercellular diffusion of small cations in the astrocytic syncytium via gap junctions became rapidly restricted after epileptiform activity. Using a transgenic mouse with astrocyte-specific expression of a pH sensor (Lck-E2GFP), we confirmed that astrocytes react to epileptiform activity with intracellular alkalization. Application of Na+/HCO3– cotransporter blocker led to the suppression of intracellular alkalization of astrocytes and to the prevention of astrocyte uncoupling and hyperactivity intensification both in vitro and in vivo. Therefore, the inhibition of astrocyte alkalization could become a promising therapeutic strategy for countering epilepsy development. SIGNIFICANCE STATEMENT We aimed to understand the mechanisms underlying the plastic change of forebrain circuits associated with the intensification of epilepsy. Here, we demonstrate that first-time exposure to only brief periods of epileptiform activity results in acute disturbance of the intercellular astrocyte network formed by gap junctions in hippocampal tissue slices from mice. Moreover, rapid clearance of K+ from the extracellular space was impaired. Epileptiform activity activated inward Na+/HCO3– cotransport in astrocytes by cell depolarization, resulting in their alkalization. Our data suggest that alkaline pH shifts in astrocytes lead to gap junction uncoupling, hampering K+ clearance, and thereby to exacerbation of epilepsy. Pharmacological intervention could become a promising new strategy to dampen neuronal hyperexcitability and epileptogenesis.

Microglia proliferation plays distinct roles in acquired epilepsy depending on disease stages

Abstract: Objective Microgliosis occurs in animal models of acquired epilepsy and in patients. It includes cell proliferation that is associated with seizure frequency and decreased neuronal cells in human epilepsy. The role of microglia proliferation in the development of acquired epilepsy is unknown; thus, we examined its contribution to spontaneous seizure, neurodegeneration, and cognitive deficits in different disease phases. Methods We used a model of acquired epilepsy triggered by intra-amygdala kainic acid in C57BL6N adult male mice. Mice were electroencephalographically (EEG) monitored (24/7) during status epilepticus and in early and chronic disease. Microglia proliferation was blocked by GW2580, a selective CSF1 receptor inhibitor, supplemented in the diet for 21 days from status epilepticus onset. Then, mice were returned to placebo diet until experiment completion. Control mice were exposed to status epilepticus and fed with placebo diet. Experimental mice were tested in the novel object recognition test (NORT) and in Barnes maze, and compared to control and sham mice. At the end of the behavioral test, mice were killed for brain histopathological analysis. Additionally, seizure baseline was monitored in chronic epileptic mice, then mice were fed for 14 days with GW2580 or placebo diet under 24/7 EEG recording. Results GW2580 prevented microglia proliferation in mice undergoing epilepsy, whereas it did not affect microglia or basal excitatory neurotransmission in the hippocampus of naive mice. Mice with occluded microglia proliferation during early disease development underwent status epilepticus and subsequent epilepsy similar to placebo diet mice, and were similarly impaired in NORT, with improvement in Barnes maze. GW2580-treated mice displayed neuroprotection in the hippocampus. In contrast, blockade of microglia proliferation in chronic epileptic mice resulted in spontaneous seizure reduction versus placebo mice. Significance Microglia proliferation during early disease contributes to neurodegeneration, whereas in late chronic disease it contributes to seizures. Timely pharmacological interference with microglia proliferation may offer a potential target for improving disease outcomes.

Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies

Abstract: Hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to mutations in genes along the PI3K-mTOR pathway and the GATOR1 complex causes a spectrum of neurodevelopmental disorders (termed mTORopathies) associated with malformation of cortical development and intractable epilepsy. Despite these gene variants’ converging impact on mTORC1 activity, emerging findings suggest that these variants contribute to epilepsy through both mTORC1-dependent and -independent mechanisms. Here, we review the literature on in utero electroporation-based animal models of mTORopathies, which recapitulate the brain mosaic pattern of mTORC1 hyperactivity, and compare the effects of distinct PI3K-mTOR pathway and GATOR1 complex gene variants on cortical development and epilepsy. We report the outcomes on cortical pyramidal neuronal placement, morphology, and electrophysiological phenotypes, and discuss some of the converging and diverging mechanisms responsible for these alterations and their contribution to epileptogenesis. We also discuss potential therapeutic strategies for epilepsy, beyond mTORC1 inhibition with rapamycin or everolimus, that could offer personalized medicine based on the gene variant.

Multi-omics analysis suggests enhanced epileptogenesis in the Cornu Ammonis 3 of the pilocarpine model of mesial temporal lobe epilepsy.

Abstract: Mesial temporal lobe epilepsy (MTLE) is a chronic neurological disorder characterized by the occurrence of seizures, and histopathological abnormalities in the mesial temporal lobe structures, mainly hippocampal sclerosis (HS). We used a multi-omics approach to determine the profile of transcript and protein expression in the dorsal and ventral hippocampal dentate gyrus (DG) and Cornu Ammonis 3 (CA3) in an animal model of MTLE induced by pilocarpine. We performed label-free proteomics and RNAseq from laser-microdissected tissue isolated from pilocarpine-induced Wistar rats. We divided the DG and CA3 into dorsal and ventral areas and analyzed them separately. We performed a data integration analysis and evaluated enriched signaling pathways, as well as the integrated networks generated based on the gene ontology processes. Our results indicate differences in the transcriptomic and proteomic profiles among the DG and the CA3 subfields of the hippocampus. Moreover, our data suggest that epileptogenesis is enhanced in the CA3 region when compared to the DG, with most abnormalities in transcript and protein levels occurring in the CA3. Furthermore, our results show that the epileptogenesis in the pilocarpine model involves predominantly abnormal regulation of excitatory neuronal mechanisms mediated by N-methyl D-aspartate (NMDA) receptors, changes in the serotonin signaling, and neuronal activity controlled by calcium/calmodulin-dependent protein kinase (CaMK) regulation and leucine-rich repeat kinase 2 (LRRK2)/WNT signaling pathways.

Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer's disease

Abstract: Alzheimer's disease (AD) can increase the risk of epilepsy by up to 10-fold compared to healthy age-matched controls. However, the pathological mechanisms that underlie this increased risk are poorly understood. Because disruption in brain glutamate homeostasis has been implicated in both AD and epilepsy, this might play a mechanistic role in the pathogenesis of epilepsy in AD. Prior to the formation of amyloid beta (Aβ) plaques, the brain can undergo pathological changes as a result of increased production of amyloid precursor protein (APP) and Aβ oligomers. Impairments in the glutamate uptake ability of astrocytes due to astrogliosis are hypothesized to be an early event occurring before Aβ plaque formation. Astrogliosis may increase the susceptibility to epileptogenesis of the brain via accumulation of extracellular glutamate and resulting excitotoxicity. Here we hypothesize that Aβ oligomers and proinflammatory cytokines can cause astrogliosis and accumulation of extracellular glutamate, which then contribute to the pathogenesis of epilepsy in AD. In this review article, we consider the evidence supporting a potential role of dysfunction of the glutamate-glutamine cycle and the astrocyte in the pathogenesis of epilepsy in AD.

The Good, the Bad, and the Deadly: Adenosinergic Mechanisms Underlying Sudden Unexpected Death in Epilepsy

Abstract: Adenosine is an inhibitory modulator of neuronal excitability. Neuronal activity results in increased adenosine release, thereby constraining excessive excitation. The exceptionally high neuronal activity of a seizure results in a surge in extracellular adenosine to concentrations many-fold higher than would be observed under normal conditions. In this review, we discuss the multifarious effects of adenosine signaling in the context of epilepsy, with emphasis on sudden unexpected death in epilepsy (SUDEP). We describe and categorize the beneficial, detrimental, and potentially deadly aspects of adenosine signaling. The good or beneficial characteristics of adenosine signaling in the context of seizures include: (1) its direct effect on seizure termination and the prevention of status epilepticus; (2) the vasodilatory effect of adenosine, potentially counteracting postictal vasoconstriction; (3) its neuroprotective effects under hypoxic conditions; and (4) its disease modifying antiepileptogenic effect. The bad or detrimental effects of adenosine signaling include: (1) its capacity to suppress breathing and contribute to peri-ictal respiratory dysfunction; (2) its contribution to postictal generalized EEG suppression (PGES); (3) the prolonged increase in extracellular adenosine following spreading depolarization waves may contribute to postictal neuronal dysfunction; (4) the excitatory effects of A2A receptor activation is thought to exacerbate seizures in some instances; and (5) its potential contributions to sleep alterations in epilepsy. Finally, the adverse effects of adenosine signaling may potentiate a deadly outcome in the form of SUDEP by suppressing breathing and arousal in the postictal period. Evidence from animal models suggests that excessive postictal adenosine signaling contributes to the pathophysiology of SUDEP. The goal of this review is to discuss the beneficial, harmful, and potentially deadly roles that adenosine plays in the context of epilepsy and to identify crucial gaps in knowledge where further investigation is necessary. By better understanding adenosine dynamics, we may gain insights into the treatment of epilepsy and the prevention of SUDEP.

Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review.

Abstract: Epilepsy is a chronic neurological disorder characterized by recurring spontaneous seizures. Drug resistance appears in 30% of patients and it can lead to premature death, brain damage or a reduced quality of life. The purpose of the study was to analyze the drug resistance mechanisms, especially neuroinflammation, in the epileptogenesis. The information bases of biomedical literature Scopus, PubMed, Google Scholar and SciVerse were used. To obtain full-text documents, electronic resources of PubMed Central and Research Gate were used. The article examines the recent research of the mechanisms of drug resistance in epilepsy and discusses the hypotheses of drug resistance development (genetic, epigenetic, target hypothesis, etc.). Drug-resistant epilepsy is associated with neuroinflammatory, autoimmune and neurodegenerative processes. Neuroinflammation causes immune, pathophysiological, biochemical and psychological consequences. Focal or systemic unregulated inflammatory processes lead to the formation of aberrant neural connections and hyperexcitable neural networks. Inflammatory mediators affect the endothelium of cerebral vessels, destroy contacts between endothelial cells and induce abnormal angiogenesis (the formation of “leaky” vessels), thereby affecting the blood–brain barrier permeability. Thus, the analysis of pro-inflammatory and other components of epileptogenesis can contribute to the further development of the therapeutic treatment of drug-resistant epilepsy.

Proteomic differences in the hippocampus and cortex of epilepsy brain tissue.

Abstract: Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioural disorders, and increased mortality from direct (e.g. sudden unexpected death in epilepsy, accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signalling networks associated with seizures in epilepsy with a broad range of aetiologies, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry was performed on the hippocampal cornu ammonis 1-3 region (CA1-3), frontal cortex and dentate gyrus microdissected from epilepsy and control cases (n = 14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1 - 3 region, 296 proteins in the frontal cortex and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signalling and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein subunit beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signalling and G-protein-coupled receptors in epilepsy. Our results provide insights into common molecular mechanisms underlying epilepsy across various aetiologies, which may allow for novel targeted therapeutic strategies.

Stress-Associated Molecular and Cellular Hippocampal Mechanisms Common for Epilepsy and Comorbid Depressive Disorders.

Abstract: The review discusses molecular and cellular mechanisms common to the temporal lobe epileptogenesis/epilepsy and depressive disorders. Comorbid temporal lobe epilepsy and depression are associated with dysfunction of the hypothalamic-pituitary-adrenocortical axis. Excessive glucocorticoids disrupt the function and impair the structure of the hippocampus, a brain region key to learning, memory, and emotions. Selective vulnerability of the hippocampus to stress, mediated by the reception of glucocorticoid hormones secreted during stress, is the price of the high functional plasticity and pleiotropy of this limbic structure. Common molecular and cellular mechanisms include the dysfunction of glucocorticoid receptors, neurotransmitters, and neurotrophic factors, development of neuroinflammation, leading to neurodegeneration and loss of hippocampal neurons, as well as disturbances in neurogenesis in the subgranular neurogenic niche and formation of aberrant neural networks. These glucocorticoid-dependent processes underlie altered stress response and the development of chronic stress-induced comorbid pathologies, in particular, temporal lobe epilepsy and depressive disorders.