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

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-1ß, 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.

Desynchronosis: Types, Main Mechanisms, Role in the Pathogenesis of Epilepsy and Other Diseases: A Literature Review.

Circadian information is stored in mammalian tissues by an autonomous network of transcriptional feedback loops that have evolved to optimally regulate tissue-specific functions. Currently, stable circadian rhythms of the expression of clock genes (Bmal1/Per2/Cry1, etc.), hormones, and metabolic genes (Glut4/leptin, etc.) have been demonstrated. Desynchronoses are disorders of the body's biorhythms, where the direction and degree of shift of various indicators of the oscillatory process are disturbed. Desynchronosis can be caused by natural conditions or man-made causes. The disruption of circadian rhythms is a risk factor for the appearance of physiological and behavioral disorders and the development of diseases, including epilepsy, and metabolic and oncological diseases. Evidence suggests that seizure activity in the epilepsy phenotype is associated with circadian dysfunction. Interactions between epilepsy and circadian rhythms may be mediated through melatonin, sleep-wake cycles, and clock genes. The correction of circadian dysfunction can lead to a decrease in seizure activity and vice versa. Currently, attempts are being made to pharmacologically correct desynchronosis and related psycho-emotional disorders, as well as combined somatic pathology. On the other hand, the normalization of the light regimen, the regulation of sleep-wake times, and phototherapy as additions to standard treatment can speed up the recovery of patients with various diseases.

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

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.