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

Abstract

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.

Identification of hub genes significantly linked to temporal lobe epilepsy and apoptosis via bioinformatics analysis

“…Previous studies have found that epilepsy is closely related to apoptosis, but the mechanisms involved are not yet fully understood ( Sokolova et al, 2022 ). The current study speculates that the mechanism may be closely related to the development of neuroinflammation and the elevation of pro-inflammatory factors (TNF-α, NF-kB, IL-1β and IL-6) ( Fuller et al, 2020 ; Sah et al, 2021 ; Yamanaka et al, 2021 ).…”

Neuroinflammatory Dysfunction of the Blood–Brain Barrier and Basement Membrane Dysplasia Play a Role in the Development of Drug-Resistant Epilepsy

“…From our previous results, it can be seen that in the cortex of the temporal lobe of DRE patients, neuroinflammatory processes occur, including a high expression of TNF- α and FAS by immunocompetent cells of the nervous tissue. In the white matter, these processes are also present but less intense [ 13 ]. At the same time, there is the previously shown increased lymphocytic infiltration.…”

“…Neuroinflammation in epilepsy foci, which is combined with the development of glioneuronal apoptosis, affects angiogenesis and BBB permeability and creates conditions for the development of drug resistance and the progression of epilepsy [ 13 , 14 ].…”

“…The increased outflow of AEDs leads to a decrease in the absorption of the drug by the brain and, as a result, to conditional resistance [ 10 , 14 ]. The third way involves the modification of voltage-dependent ion channels by inflammatory mediators penetrating through the damaged BBB, which leads to a decrease in the sensitivity of these receptors to the drugs [ 13 ].…”

Thalidomide Attenuates Epileptogenesis and Seizures by Decreasing Brain Inflammation in Lithium Pilocarpine Rat Model

“…There is evidence that neuroinflammation plays a key part in epileptogenesis [ 21 , 22 ]. In turn, it affects other processes such as neurogenesis and leads to abnormal reorganization of neuronal networks, mainly in the hippocampus, further promoting neuronal death [ 23 , 24 , 25 ]. Consequently, inhibiting neuroinflammation may be effective for the reduction or even prevention of epileptogenesis.…”