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].
- Sitnikova E. Adrenergic mechanisms of absence status epilepticus Front. Neurol. 2023 14: 1298310. DOI: 10.3389/fneur.2023.1298310
- 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 .
- 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].
- Sitnikova E. Adrenergic mechanisms of absence status epilepticus Front. Neurol. 2023 14: 1298310. DOI: 10.3389/fneur.2023.1298310
- 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 .
- 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
Small extracellular vesicles (sEVs) properties and sEVs composition are far from being well-studied for now, especially in the context of mental disorders. To elucidate the role of sEVs in disease we performed a quantitative analysis of the blood sEV in patients with focal epilepsy and patients with focal epilepsy with depression, psychogenic non-epileptic seizures with depression, pure depression, and bipolar affective disorder with the current depressive episode (cDE). Small EVs were isolated from the serum by gel filtration or PEG precipitation, and both methods showed very similar results. Subsequently, we precipitated neuronal sEVs and quantified it with several methods. Activity of lysosomal enzymes was determined in the sEVs fraction. The concentration of the blood sEVs in patients with depression, focal epilepsy, or depression with focal epilepsy was higher than in healthy controls. No difference was found between patients and controls in terms of neuronal sEVs concentration. Another finding of our work is that sEVs in the serum of patients contains various lysosomal enzymes. We suppose that the concentration of the blood sEVs in patients with depression or epilepsy is higher due to the sEVs secretion by the immune cells. Finding sEVs in the blood of patients with depression and focal epilepsy grants validity for future attempts to use sEVs as diagnostic tools for these disorders.
Extracellular vesicles (EVs) are a new and actively developing area of modern experimental and theoretical biology, which attracts researchers primarily by the possibility of using EVs as diagnostic biomarkers and therapeutic agents. Currently, the greatest amount of data has been accumulated on small extracellular vesicles (sEVs) – exosomes, vesicles of endosomal origin, and ectosomes (previously known as microvesicles), which are the product of direct budding from the plasma membrane. In this review, we address the major steps in the biogenesis of exosomes and ectosomes, the major processes of intracellular membrane trafficking, and signaling involving sEVs. The role of the sEVs in the physiology and pathophysiology of the nervous system is also discussed, as well as many promising aspects of the study of sEVs biology.