Neuroglial apoptosis and neuroinflammation play an important role in epileptogenesis. The aim of this study is to evaluate neuronal and glial apoptosis in association with neuroinflammation in brain epileptic focus and inflammatory changes in blood in patients with focal drug-resistant epilepsy (DRE). Pathological changes in the temporal lobe in epilepsy (histology, transmission electron microscopy), levels of apoptotic and neuroinflammatory proteins: active caspase-3 (immunohistochemistry), full-length form caspase-3, caspase-9, FAS, FAS-L, NF-kB, TNF-α, p53 (Western blot), and cytokine levels in blood: IL-1β, IL-2, IL-4, IL-7, TNF-α, etc. (multiplex analysis) were studied. In the present work, ultrastructural and immunohistochemical apoptotic signs were found in neurons and oligodendrocytes in the temporal lobe of DRE patients. Levels of proinflammatory cytokines that play a role in apoptosis (TNF-α, FAS, NF-kB) were increased. The blood concentration of IL-4, IL-7, TNF-α is increased and IL-2 is reduced. Oligodendroglial apoptosis has been shown to play an important role in DRE pathogenesis and to explain demyelination. Thus, a comprehensive analysis of revealed changes in the blood and brain in DRE patients showed the neuroinflammation in the epileptic focus, which was combined with the development of apoptosis of glial cells and neurons. This creates conditions for the development of drug resistance and the epilepsy progression.

https://www.mdpi.com/1422-0067/23/20/12561/pdf?version=1666599565

Relationship between Neuroglial Apoptosis and Neuroinflammation in the Epileptic Focus of the Brain and in the Blood of Patients with Drug-Resistant Epilepsy

The chapter focuses on how different cutting-edge techniques can be used to study electrophysiological, pathomorphological, and biochemical changes in the “epileptic focus” area of the cerebral cortex and white matter to see how epileptic seizures become drug-resistant and how it affects the other regions of the brain. The authors highlight the significance of neuroinflammation and apoptosis in the epilepsy pathogenesis providing EEG characteristics and describing structural changes in the cortex and white matter under such conditions as focal cortical dysplasia and epileptic leukoencephalopathy. Particular focus is given to structural and functional changes in the hippocampus and the role of hippocampal sclerosis in epilepsy. Key conceptions regarding the epileptic focus formation are outlined. 

/pdf/epileptic-focus-in-drug-resistant-epilepsy-structure-2dkn6vjs.pdf

Epileptic Focus in Drug-Resistant Epilepsy: Structure, Organization, and Pathophysiology

The study of glioneuronal apoptosis and neuroinflammation is extremely important for understanding the causes of epilepsy. Currently, the focus is on neuronal apoptosis and certain aspects of neuroinflammation, while glial apoptosis remains poorly understood. Objective : to evaluate neuronal and glial apoptosis in conjunction with neuroinflammation in the area of the epileptic focus in patients with focal drug-resistant epilepsy (DRE). Material and methods . Biopsy specimens of the cortex and white matter of the temporal lobe of the brain from 30 patients with focal DRE due to focal cortical dysplasia were studied. We evaluated pathological changes and structural signs of apoptosis, levels of apoptotic and pro-inflam-matory factors such as caspase-3, caspase-9, FAS, FAS ligand (FAS-L), tumor necrosis factor α (TNFα), p53, nuclear factor κB (NF-κB). Histological methods, transmission electron microscopy (TEM), immunohistochemical study (IHC), and Western blot (WB) were used. The comparison group consisted of 21 people without epilepsy and brain involvement. Results . In DRE patients IHC revealed the expression of active caspase-3 in single neurons (20% of cases) and in gliocytes of the cerebral cortex and white matter (100% of cases). TEM revealed ultrastructural signs of apoptosis in all cases in neurons and oligodendrocytes. The WB of the epileptic focus showed an increased expression of the apoptotic factors caspase-9, FAS, p53 and pro-inflammatory factors TNFα, NF-κB. Conclusion . The results obtained indicate the presence of associated apoptosis and neuroinflammation processes of in DRE. Glial apoptosis is actively involved in epileptogenesis. The main part of apoptotic glia is oligodendrocytes, which explains the well-known phenomenon of myelin damage in epilepsy. Along with neuronal apoptosis, oligodendrocyte apoptosis together with neuroinflammation forms a self-sustaining pathological focus, which contributes to the progression of the disease and the occurrence of relapses. 

/pdf/glioneuronal-apoptosis-and-neuroinflammation-in-drug-2cnhzqwh.pdf

Glioneuronal apoptosis and neuroinflammation in drug resistant temporal lobe epilepsy

Current antiepileptic strategies aim to normalize the interaction
of the excitatory and inhibitory systems, which is ineffective in
treating patients with drug-resistant epilepsy. Neuroinflammatory processes
in the epileptic focus and its perifocal area can trigger apoptosis
and also contribute to the development of drug resistance. The level
of pro- and anti-apoptotic proteins (p-NF-kB, TNF-α, p53, FAS, caspase-3,
caspase-9) was analyzed in intraoperative biopsies of the temporal
lobe gray and white matter in the brain of patients with drug-resistant
epilepsy. An increased level of pro-apoptotic proteins was revealed
in the cortex and perifocal area’s white matter against the background
of an imbalance of protective anti-apoptotic proteins. It appears
that the activation of the extrinsic pathway of apoptosis occurs
in the perifocal area, while in the epileptic focus, there are proteins
responsible for the activation of the anti-apoptotic survival pathways.
Active neuroinflammation in the epileptic focus and perifocal area
of the temporal lobe may contribute to the development of the resistance
to antiepileptic drugs and the progression of neurodegeneration in
such patients.

L. K. Khuzhakhmetova

Papers

Markers of Neuroinflammation and Apoptosis in the Temporal Lobe of Patients with Drug-Resistant Epilepsy