Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy.

Epilepsy is one of the common neurological diseases that affects not only adults but also infants and children. Because epilepsy has been studied for a long time, there are several pharmacologically effective anticonvulsants, which, however, are not suitable as therapy for all patients. The genesis of epilepsy has been extensively investigated in terms of its occurrence after injury and as a concomitant disease with various brain diseases, such as tumors, ischemic events, etc. However, in the last decades, there are multiple reports that both genetic and epigenetic factors play an important role in epileptogenesis. Therefore, there is a need for further identification of genes and loci that can be associated with higher susceptibility to epileptic seizures. Use of mouse knockout models of epileptogenesis is very informative, but it has its limitations. One of them is due to the fact that complete deletion of a gene is not, in many cases, similar to human epilepsy-associated syndromes. Another approach to generating mouse models of epilepsy is N-Ethyl-N-nitrosourea (ENU)-directed mutagenesis. Recently, using this approach, we generated a novel mouse strain, soc (socrates, formerly s8-3), with epileptiform activity. Using molecular biology methods, calcium neuroimaging, and immunocytochemistry, we were able to characterize the strain. Neurons isolated from soc mutant brains retain the ability to differentiate in vitro and form a network. However, soc mutant neurons are characterized by increased spontaneous excitation activity. They also demonstrate a high degree of Ca2+ activity compared to WT neurons. Additionally, they show increased expression of NMDA receptors, decreased expression of the Ca2+-conducting GluA2 subunit of AMPA receptors, suppressed expression of phosphoinositol 3-kinase, and BK channels of the cytoplasmic membrane involved in protection against epileptogenesis. During embryonic and postnatal development, the expression of several genes encoding ion channels is downregulated in vivo, as well. Our data indicate that soc mutation causes a disruption of the excitation-inhibition balance in the brain, and it can serve as a mouse model of epilepsy.

Heart Dysfunction in Essential Hypertension Depends on Systemic Proinflammatory Influences: A Retrospective Clinical Pathophysiological Study.

Low-intensity systemic inflammation is an important element of heart failure pathogenesis. The aim of this study is to assess proinflammatory status serum indicators (C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6)) in middle-aged males (M) and females (F) with essential hypertension (HTN) depending on left ventricular (LV) diastolic dysfunction (LVDD). The main group comprised 55 M and 49 F with the first- to second-severity grade HTN with mild heart failure and a preserved LV ejection fraction ≥50%. Patients had sinus rhythm, first or second-severity degree LVDD, LV hypertrophy, left atrium dilatation, and NT-proBNP > 125 pg/mL. Comparison group: 30 hypertensives without cardiac dysfunction; control group: 31 normotensives. Quantitative features were compared using the Mann−Whitney test, median χ2, ANOVA module. Spearman's rank correlation coefficients were determined to identify the relationship between the proinflammatory pattern and exercise tolerance. Hypertensive M had markedly higher CRP, TNF-α, and IL-6 levels compared to F. All mean values corresponded to reference range. In patients with second-degree LVDD, CRP, TNF-α, and IL-6 levels were significantly greater than in subjects with first-degree LVDD (both within M and within F samples). Significant negative associations between CRP, IL-6, and TNF-α levels and the 6 min walk test existed in hypertensive M and F. The study demonstrated a close relationship between the proinflammatory pattern and LVDD and exercise tolerance indicators, regardless of the hypertensive patient's sex.

Sip-1 mutations cause disturbances in the activity of NMDA- and AMPA-, but not kainate receptors of neurons in the cerebral cortex.

Smad-interacting protein-1 (Sip1) [Zinc finger homeobox (Zfhx1b), Zeb2] is a transcription factor implicated in the genesis of Mowat-Wilson syndrome (MWS) in humans. MWS is a rare genetic autosomal dominant disease caused by a mutation in the Sip1 gene (aka Zeb2 or Zfhx1b) mapped to 2q22.3 locus. MWS affects 1 in every 50-100 newborns worldwide. It is characterized by mental retardation, small stature, typical facial abnormalities as well as disturbances in the development of the cardio-vascular and renal systems as well as some other organs. Sip1 mutations cause abnormal neurogenesis in the brain during development as well as susceptibility to epileptic seizures. In the current study we investigated the role of the Sip1 gene in the activity of NMDA-, AMPA- and KA- receptors. We showed that a particular Sip1 mutation in the mouse causes changes in the activity of both NMDA- and AMPA- receptors in the neocortical neurons in vitro. We demonstrate that neocortical neurons that have only one copy of Sip1 (heterozygous, Sip1fI/wt), are more sensitive to both NMDA- and AMPA- receptors agonists as compared to wild type neurons (Sip1wt/wt). This is reflected in higher amplitudes of agonist induced Ca2+ signals as well as a lower half maximal effective concentration (ЕC50). In contrast, neurons from homozygous Sip1 mice (Sip1fI/fI), demonstrate higher resistance to these respective receptor agonists. This is reflected in lower amplitudes of Ca2+-responses and so a higher concentration of receptor activators is required for activation.