Epilepsy

A recently published article by researchers from the IHNA&NPh RAS and the Moscow Research and Clinical Center for Neuropsychiatry raises new and interesting questions in the study of small extracellular vesicles (sEVs) in human blood. Previously, the team, using four different methods, had shown significant increase in the concentration of sEVs in the blood of patients with depression compared to healthy volunteers, and the followed work was intended to clarify the source of these “extra” vesicles in depression. In addition, the authors compared sEVs content in the blood of patients with a wide range of pathologies, including epilepsy, epilepsy with depression, bipolar affective disorder with a current depressive episode, and psychogenic nonepileptic seizures with depression. Small EVs were isolated from patient serum using gel filtration or polyethylene glycol (PEG) precipitation, and both methods showed very similar results. It turned out that in patients with depression, epilepsy, or epilepsy with depression, the total level of mBB in the blood is increased by up to two times compared to healthy volunteers. The authors of the work were able to go further and isolate the fraction of sEVs of neuronal origin (in the blood this is approximately every one hundred and fiftieth vesicle) in these patients, but no difference in the concentration of neuronal sEVs was found between any groups. The question of where the “extra” sEVs in the patients’ blood came from remains open. The authors suggest that the source of these sEVs are immune cells. However, the authors did discover at least one new finding that sheds light on the biogenesis of sEVs. It turned out that sEVs in the serum of both patients and healthy volunteers contain various lysosomal enzymes - and this is a hint that the contents of sEVs may reflect the state of the intracellular endolysosomal system.

On January 7, 2024, Dr. Evgenia Sitnikova's review on behavioral and neuro-cognitive comorbidities in rats with a genetic predisposition to absence epilepsy was published in the journal Biomedicines. Absence epilepsy is a non-convulsive type of epilepsy characterized by a sudden decrease in consciousness. Absence epilepsy is a disorder of the thalamo-cortical system, and it is accompanied by neurocognitive comorbidities. Absence-like seizures have been observed in many strains of albino laboratory rats, including Wistar, Sprague–Dawley, and Long Evans. Spontaneous absence-like seizures are common in adult Wistar rats, so caution should be exercised when using Wistar rats as controls. The specially bred GAERS (Genetic Absence Epilepsy Rats from Strasbourg) and WAG/Rij (Wistar Albino Rats from Rijswijk) rats are genetic models of absence epilepsy, which show behavioral and cognitive impairments similar to those of patients with absence epilepsy. In WAG/Rij rats, deficit of executive function and impairment of memory are associated with epilepsy severity. This review discusses depressive and anxiety-like behavior in GAERS and WAG/Rij rats, sex differences in concomitant cognitive impairment, and high emotionality in genetically predisposed rats. In order to better comprehend the causes of neurocognitive dysfunction in absence epilepsy, the author suggests using the concept of the "cognitive thalamus".

Keywords: genetic animal models; spontaneous absence epilepsy; drug-naive rats; fear-motivated learning; anxiety-like symptoms; depression-like symptoms; cognitive thalamus

Epilepsy is a chronic disease characterized not only by disturbances in neural activity, but also by significant changes in glial cells. Leading researcher at our institute, Doctor of Biological Sciences. E, Y. Sitnikova, together with colleagues from Istanbul University and Acibadem Mehmet Ali Aydinlar University (Istanbul, Turkey), published a review where they systematized dysfunction of astrocytes in the development of epilepsy, including epileptogenesis (generation of seizure activity) and ictogenesis (generalization of seizure activity). Special attention is paid to new strategies for targeted therapy of epilepsy aimed at regulating the functions of astrocytic neuroglia: (1) selective impact on neuroglial molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) modulation of gliotransmission; (4) effects on the astrocytic system Kir4.1-BDNF; (5) modulation of astrocytic Na+/K+/ATPase activity; (6) correction of hypo- or hypermethylation of candidate genes in astrocyte DNA; (7) effects on astrocytic gap junction regulators; (8) effects on astrocytic adenosine kinase (the main enzyme that metabolizes adenosine); and (9) targeting neuroinflammation involving microglia and astrocytes.

Details are outlined in this article, published in July 2023 in the journal Frontiers in Molecular Neuroscience.

The mother's diet during the perinatal period is the most important early environmental factor that, through epigenetic modifications, can cause changes in gene expression and, as a consequence, the phenotype of the offspring. Employees of the Institute of Higher Inspectorate and Scientific Branch of the Russian Academy of Sciences and the Institute of Molecular Genetics of the Russian Academy of Sciences were the first to show that increased DNA methylation in the early stages of ontogenesis using a maternal diet enriched with methyl supplements (MAD) suppresses the manifestation of genetic absence epilepsy and comorbid depression in the offspring of WAG/Rij rats . The beneficial phenotypic effect of maternal MOD was accompanied by increased expression of pathogenetically significant genes - the hcn1 ion channel gene and the DNA methyltransferase 1 (dnmt1) gene in the somatosensory cortex and hippocampus, as well as the hcn1, dnmt1 and tyrosine hydroxylase (th) genes in the nucleus accumbens. The therapeutic effect of maternal MOD was similar to that of ethosuximide, the first-choice drug for the treatment of absence epilepsy. It is assumed that maternal MOD can serve as a new preventive therapeutic strategy for epigenetic correction of absence epilepsy and comorbid depression in offspring.

 
Статья опубликована в январе 2023 года в журнале Diagnostics:
 
https://doi.org/10.3390/diagnostics13030398

There are two main types of adrenergic receptors (alpha and beta) with several subtypes in the human and animal brain. Alpha2-adrenergic receptors are of particular interest, because they are involved in the modulation of sleep and absence epilepsy. In 2023, a group of young scientists led by a senior researcher, Dr. Evgenia Sitnikova, have studied the adrenergic mechanisms of sleep and epilepsy. The results of their research were published in the International Journal of Molecular Science and Frontiers in Neurology [1, 2, 3]. Therapeutic doses of alpha2 adrenergic agonists (such as dexmedetomidine) are known to cause sedation and drug-induced sleep in humans and animals. These drugs in low doses were found to induce spike-wave activity in the electroencephalogram, i.e. manifestation of absence epilepsy, in genetically prone rats (WAG/Rij) [1, 2, 3]. А single (intraperitoneal) injection of dexmedetomidine at the dose of 0.005 mg/kg increased absence epilepsy in WAG/Rij rats (i.e., genetic model of absence epilepsy) up to status epilepticus in subjects with severe absence epilepsy, but did not cause de novo absence epilepsy in asymptomatic rats [1, 2]. Dexmedetomidine has been regularly used in clinical practice for decades, and low doses of this drug may help in the diagnosis of latent forms of absence epilepsy during EEG examination. Dexmedetomidine, along with other central alpha2-adrenergic agonists, could be a pharmacological tool for differential diagnosis. The high risk of provoking absence status should be taken into account when using alpha2-adrenergic receptor agonists in patients with absence epilepsy or with a genetic predisposition to this disease [1].

A new concept of targeted pharmacotherapy of absence epilepsy using alpha2B-adrenergic receptor antagonists was proposed based on our experimental and literature data [1, 3].

1. Sitnikova E.Adrenergic mechanisms of absence status epilepticusFront. Neurol. 2023 14: 1298310. DOI: 10.3389/fneur.2023.1298310
2. Sitnikova E., Pupikina M.,Rutskova E.Alpha2 Adrenergic Modulation of Spike-Wave Epilepsy: Experimental Study of Pro-Epileptic and Sedative Effects of Dexmedetomidine. International Journal of Molecular Sciences. 2023. 24(11): 9445. DOI: 10.3390/ijms24119445 .
3. Sitnikova E., Rutskova E., Smirnov K.Alpha2-Adrenergic Receptors as a Pharmacological Target for Spike-Wave Epilepsy. International Journal of Molecular Sciences. 2023. 24(2):1477. DOI: 10.3390/ijms24021477.

The illustration [3]licensed under CC BY 4.0. © 2023 authors

Two main types of adrenergic receptors (alpha and beta) and many subtypes have been described in the human and animal brain. Alpha2-adrenergic receptors deserve special attention because they are involved in the modulation of sleep and absence epilepsy. In 2023, a group of young scientists under the guidance of a senior mentor, Dr. Sc. E.Yu. Sitnikova began research on the adrenergic mechanisms of sleep and epilepsy, the results of which were published in the International Journal of Molecular Science and Frontiers in Neurology [1, 2, 3]. Therapeutic doses of alpha2-adrenergic agonists (eg, dexmedetomidine) are known to have a sedative effect and induce drug-induced sleep in humans and animals. These drugs in low doses cause generalized peak-wave activity on the electroencephalogram, i.e. manifestation of absence epilepsy in rats with a genetic predisposition to this disease (WAG/Rij) [1, 2, 3]. Thus, a single injection of dexmedetomidine at a dose of about 0.005 mg/kg increased absence epilepsy in WAG/Rij rats (a genetic model of absence epilepsy) up to the onset of status epilepticus in individuals with severe absence epilepsy [2], but did not cause absence epilepsy. de novo epilepsy in asymptomatic rats [1, 2]. Dexmedetomidine is regularly used in clinical practice, and can be used in low doses to diagnose latent forms of absence epilepsy [1]. The high risk of provoking absence status should be taken into account when using alpha2-adrenergic receptor agonists in patients with absence epilepsy or with a genetic predisposition to this disease [1].

Based on an analysis of our own and literature data, a new concept of targeted pharmacotherapy of absence epilepsy using alpha2B-adrenergic receptor antagonists was put forward [1, 3].

1. Sitnikova E.Adrenergic mechanisms of absence status epilepticusFront. Neurol. 2023 14: 1298310. DOI: 10.3389/fneur.2023.1298310
2. Sitnikova E., Pupikina M.,Rutskova E.Alpha2 Adrenergic Modulation of Spike-Wave Epilepsy: Experimental Study of Pro-Epileptic and Sedative Effects of Dexmedetomidine. International Journal of Molecular Sciences. 2023. 24(11): 9445. DOI: 10.3390/ijms24119445 .
3. Sitnikova E., Rutskova E., Smirnov K.Alpha2-Adrenergic Receptors as a Pharmacological Target for Spike-Wave Epilepsy. International Journal of Molecular Sciences. 2023. 24(2):1477. DOI: 10.3390/ijms24021477.

Использована иллюстрация [3] с разрешения авторов под лицензией CC BY 4.0. © 2023

In humans, early pathological activity on invasive electrocorticograms (ECoGs) and its putative association with pathomorphology in the early period of traumatic brain injury (TBI) remains obscure. Our scientists from the Laboratory of Functional Biochemistry of Nervous System assessed pathological activity on scalp electroencephalograms (EEGs) and ECoGs in patients with acute TBI, early electrophysiological changes after lateral fluid percussion brain injury (FPI), and electrophysiological correlates of hippocampal damage (microgliosis and neuronal loss), a week after TBI in rats. They revealed that epileptiform activity on ECoGs was evident in 86% of patients during the acute period of TBI, ECoGs being more sensitive to epileptiform and periodic discharges. A “brush-like” ECoG pattern superimposed over rhythmic delta activity and periodic discharge was described for the first time in acute TBI. In rats, FPI increased high-amplitude spike incidence in the neocortex and, most expressed, in the ipsilateral hippocampus, induced hippocampal microgliosis and neuronal loss, ipsilateral dentate gyrus being most vulnerable, a week after TBI. Epileptiform spike incidence correlated with microglial cell density and neuronal loss in the ipsilateral hippocampus. Based on these results, our employees concluded that epileptiform activity is frequent in the acute period of TBI period and is associated with distant hippocampal damage on a microscopic level. This damage is probably involved in late consequences of TBI. The FPI model is suitable for exploring pathogenetic mechanisms of post-traumatic disorders