Oestradiol Regulates Neuropeptide Y Release and Gene Coupling with the GABAergic and Glutamatergic Synapses in the Adult Female Rat Dentate Gyrus.

Neuropeptide Y (NPY) is an endogenous modulator of neuronal activity affecting both GABAergic and glutamatergic transmission. Previously, we found that oestradiol modifies the number of NPY immunoreactive neurones in the hippocampal dentate gyrus. In the present study, we investigated which oestrogen receptor type is responsible for these changes in the number of NPY-positive neurones. Furthermore, we determined the effects of oestrogen receptor activation on NPY release. Finally, we examined the contribution of oestrogen toward the remodelling of the GABAergic and glutamatergic gene networks in terms of coupling with Npy gene expression in ovariectomised rats. We found that activation of either oestrogen receptor type (ERα or ERß) increases the number of NPY-immunopositive neurones and enhances NPY release in the dentate gyrus. We also found that, compared to oestrogen-lacking ovariectomised rats, oestrogen replacement increases the probability of synergistic/antagonistic coupling between the Npy and GABAergic synapse genes, whereas the glutamatergic synapse genes are less likely to be coupled with Npy under similar conditions. The data together suggest that oestrogens play a critical role in the regulation of NPY system activity and are also involved in the coupling/uncoupling of the Npy gene with the GABAergic and glutamatergic synapses in the female rat dentate gyrus.

Sex-specific behavioral traits in the Brd2 mouse model of juvenile myoclonic epilepsy.

Idiopathic generalized epilepsy represents about 30-35% of all epilepsies in humans. The bromodomain BRD2 gene has been repeatedly associated with the subsyndrome of juvenile myoclonic epilepsy (JME). Our previous work determined that mice haploinsufficient in Brd2 (Brd2+/-) have increased susceptibility to provoked seizures, develop spontaneous seizures and have significantly decreased gamma-aminobutyric acid (GABA) markers in the direct basal ganglia pathway as well as in the neocortex and superior colliculus. Here, we tested male and female Brd2+/- and wild-type littermate mice in a battery of behavioral tests (open field, tube dominance test, elevated plus maze, Morris water maze and Barnes maze) to identify whether Brd2 haploinsufficiency is associated with the human behavioral patterns, the so-called JME personality. Brd2+/- females but not males consistently displayed decreased anxiety. Furthermore, we found a highly significant dominance trait (aggression) in the Brd2+/- mice compared with the wild type, more pronounced in females. Brd2+/- mice of either sex did not differ from wild-type mice in spatial learning and memory tests. Compared with wild-type littermates, we found decreased numbers of GABA neurons in the basolateral amygdala, which is consistent with the increase in aggressive behavior. Our results indicate that Brd2+/- haploinsufficient mice show no cognitive impairment but have behavioral traits similar to those found in patients with JME (recklessness, aggression). This suggests that either the BRD2 gene is directly responsible for influencing many traits of JME or it controls upstream regulators of individual phenotypes.

Prenatal corticosteroids modify glutamatergic and GABAergic synapse genomic fabric: insights from a novel animal model of infantile spasms.

Prenatal exposure to corticosteroids has long-term postnatal somatic and neurodevelopmental consequences. Animal studies indicate that corticosteroid exposure-associated alterations in the nervous system include hypothalamic function. Infants with infantile spasms, a devastating epileptic syndrome of infancy with characteristic spastic seizures, chaotic irregular waves on interictal electroencephalogram (hypsarhythmia) and mental deterioration, have decreased concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in cerebrospinal fluid, strongly suggesting hypothalamic dysfunction. We have exploited this feature to develop a model of human infantile spasms by using repeated prenatal exposure to betamethasone and a postnatal trigger of developmentally relevant spasms with NMDA. The spasms triggered in prenatally primed rats are more severe compared to prenatally saline-injected ones and respond to ACTH, a treatment of choice for infantile spasms in humans. Using autoradiography and immunohistochemistry, we have identified a link between the spasms in our model and the hypothalamus, especially the arcuate nucleus. Transcriptomic analysis of the arcuate nucleus after prenatal priming with betamethasone but before trigger of spasms indicates that prenatal betamethasone exposure down-regulates genes encoding several important proteins participating in glutamatergic and GABAergic transmission. Interestingly, there were significant sex-specific alterations after prenatal betamethasone in synapse-related gene expression but no such sex differences were found in prenatally saline-injected controls. A pairwise relevance analysis revealed that, although the synapse gene expression in controls was independent of sex, these genes form topologically distinct gene fabrics in males and females and these fabrics are altered by betamethasone in a sex-specific manner. These findings may explain the sex differences with respect to both normal behaviour and the occurrence and severity of infantile spasms. Changes in transcript expression and their coordination may contribute to a molecular substrate of permanent neurodevelopmental changes (including infantile spasms) found after prenatal exposure to corticosteroids.

[Prevention of insult with nondirective anticoagulant therapy by warfarin (warfarex) in patients with atrial fibrillation].

The aim of the study was to estimate efficiency and safety of treatment by non-direct anticoagulant--warfarex in the patients with persistent and paroxysmal forms of AF for the prevention of thromboembolic complications. 55 patients between 37 and 75 years old with atrial fibrillation (AF) were investigated. Follow-up was 2 years. Primary diseases were post myocardic cardiosclerosis, cardiomyopathy, IHD, arterial hypertension. The patients with persistent form of AF underwent treatment by warfarex. In the case of paroxysmal form of AF patients were prescribed warfarex during the first 48 hours from the beginning of paroxysm and for 3-4 weeks after cardioversion. The dose of warfarex was chosen according International Normalized Ratio (2.0-3.0). The results of the study show, that warfarex is effective and safe for the prevention of thromboembolic complications in the case of persistent and paroxysmal forms of AF.

[Clinical-hemodynamic and anti-ischemic effects ivabradine and nebivolol ischemic heart disease with left ventricular dysfunction].

The aim of this study was to examine the effectiveness of Ivabradine (available under the brandnames of Procoralan, Coralan, Corlentor, Coraxan, "Servier", France) and Nebivolol (Nebilet, "Berlin-Chemie", Germany) with combination of standard therapy in patients with coronary artery disease and left ventricular dysfunction. A total of 72 patients (mean age 57.3±4,5 years) have been observed during 6 months. Patients were divided into 3 groups (standard therapy; standard therapy and Nebilet; standard therapy and Coraxan). The results showed that Coraxan with combination therapy compared optimally reduced heart rate and ensure a proper anti-ischemic effect, expressed as reduced left ventricular dysfunction, improved the degree of congestive heart failure than the group Nebilet.

[The efficacy of propafenon in the case of supraventricular atrioventricular tachycardia].

One of the main methods the treatment of patients with supraventricular paroxysmal tachycardia remains drug therapy, which involves the prevention attacks of cardiac arrhythmias. Drugs of choice for termination and prevention of paroxysmal supraventricular tachycardia in the absence of pronounced signs structural myocardial damage is an antiarrhythmic with I C class (propafenon - propanorm). Efficacy of propafenon and its influence on the functional state of heart in patients with paroxysmal antrioventricular tachycardias was studied. It was found that propafenon is highly effective in preventing paroxysmal antrioventricular reciprocating tachycardia and atrioventricular nodal tachycardia. The drug has no negative effect on the functional state of heart.

Noradrenergic modulation of seizure activity.

The mechanisms underlying pathogenesis of epileptic rections have been studied insufficiently as yet. Therefore, it is considered that determining the structures, transmitters, and receptors of the brain, which putatively produce development and intensity modulation of the convulsions, is highly important. The locus coeruleus is a norepinephrinic structure and an endogenous modulator of epilepsy, determining a role of which in a course of seizure reactions is an important problem of epileptology. The goal of the study was assessment of importance of the norepinephrine synapses in development of the local hippocampal seizure activity. The studies were carried out in adult rats, in conditions of chronic experiments. Influences of microinjections of agonist (clonidine) and antagonist (yohimbine) of the alpha-2 norepinephrine receptors on a course of local hippocampal seizure reactions (without behavioral manifestation), have been evaluated. It was found that microinjection of alpha-2 norepinephrine receptors' agonist determined a blockage of the local hippocampal seizures, while alpha-2 norepinephrine receptors' antagonist increased the seizures' power. It is suggested that the effects of locus coeruleus are determined by activation of the alpha-2 norepinephrine receptors.

[Mechanisms involved in anticonvulsive effect of pregnancy in an animal model of epilepsy].

Interrelation between pregnancy and epilepsy is one of the pressing problems of current neurology. Those mechanisms, which suppress or amplify the seizure reactions in pregnancy, have not been yet determined experimentally. Investigation of the interrelation between the epileptic fits and pregnancy in women is complicated by the bioethical considerations, as well as by the antiepileptic therapy. Therefore, in order to solve this problem, an implementing the animal models seems expedient; moreover that this problem is scarcely investigated so far. The goal of present work was investigation of impact of gestation and the postpartum period on initiation and development of convulsive reactions in the experimental animal model. Epileptic reactions were significantly suppressed during gestation (2 and 3 weeks). The data on the changes are concerned behavioral reactions and EEG seizure activity. Therefore, generalization of the seizure activity is blocked during pregnancy.

Influence of hypothalamic stimulation on the development of status epilepticus in rats.

The main objectives of the present study were to explore whether emotional behavior, elicited by stimulation of the dorso-medial hypothalamus, can influence seizure development during self-sustained status epilepticus (SSSE). The study was conducted on animal models. The results suggest that increased inhibition in the hippocampal neurons during dorsomedial hypothalamic stimulation may trigger the mechanisms preventing the epileptiform activity and that hippocampal theta rhythm is a physiological state, which opposes its involvement into seizures. It was concluded that activation of the dorsomedial hypothalamus, as well as emotional behavior (anxiety/fear) retard development of the seizures experimentally induced SSSE by limbic stimulation.

Interictal emotional state and epilepsy.

The main objectives of the present study were twofold: to explore whether emotional behavior, elicited by stimulation of the hypothalamus, can influence seizure development during kindling epileptogenesis; to determine whether such stimulation can alter the expression of generalized convulsions when the fully epileptic syndrome has been established beforehand.The kindling process has been used as an animal model for studies of epilepsy. The findings indicate that stimulation in the hypothalamus, which determines fear, anxiety, and escape responses, with concomitant hippocampal theta, can significantly dampen the course of epileptogenesis. The emotional behaviors elicited by stimulation of the dorsomedial hypothalamus can suppress the development of generalized motor limbic convulsions during epileptogenesis, as well as dampen seizure expression in already established limbic epilepsy. It is assumed that the emotional disturbances can be considered as the emergence of instinctive behavior with an adaptive significance of defense and as a by-product of the inhibitory processes that build up to protect the occurrence of future seizures.

[Development of audiogenic kindling during the gestation period].

Some peculiarities of audiogenic kindling were studied in rats with genetically determined epileptic seizures during gestation period. In the period of gestation the development of audiogenic kindling in response to repetitive acoustic stimulation is markedly reduced. This indicates the strengthening of inhibitory processes in the brain. It is supposed that in the period of gestation in rats with genetically determined audiogenic seizures excess of sexual hormones and enhancement of GABA-ergic transmission causes marked reduction of development of audiogenic kindling.