THE MECHANISMS CONTRIBUTING TO THE DEVELOPMENT OF ARTERIAL HYPERTENSION, ADVANTAGES AND DISADVANTAGES OF THE ASSOCIATED EXPERIMENTAL MODELS (REVIEW).

Arterial hypertension is one of most common diseases in the world with variable etiologies, yet the exact cause cannot always be found. It is classified as essential (primary) or secondary hypertension. Unlike secondary hypertension, primary hypertension has no known cause. Animal models have been used to investigate the pathophysiology of the disease and for testing new treatment strategies. Using animal models to better understand the etiology, prevention, and treatment of hypertension depends on their accuracy for representing human disease. Current challenges in this field include the development of models mimicking the common hypertensive syndromes and the development of new prevention and treatment strategies. Animal models may be beneficial to address these challenges. While choosing the appropriate model of hypertension, scientists need to choose between small and large animal models. The research scope and objectives, experimental expenses, animal welfare, and practical suitability should all be considered. The advantages and disadvantages of these models need to be assessed in detail in order to select the best model. From the many models of arterial hypertension, it can be distinguish different models of essential and secondary arterial hypertension. Of the essential arterial hypertension three main methods are noteworthy, pharmacological, environmental conditions, and genetic model. As for secondary hypertension, it can be challenged by physical methods such as renal artery clipping or its microembolization.

ENDOCANNABINOIDS RECEPTORS MEDIATED CENTRAL AND PERIPHERAL EFFECTS (REVIEW).

The present article is devoted to the action of endocannabinoids via stimulation of their corresponding receptors. It is well established the existence of three type of endocannabinoids (ECS) such as anandamide (AA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PE) providing their effects by activation of CB1 and CB2 ECS receptors. AA is a partial agonist for both receptors, having more affinity for CB1 receptors, while 2-AG reveals an equal agonistic properties to both of them in contrast to PE, which may bind to a unidental "CB2-like" receptors. CB1 receptors are distributed in the central and peripheral nervous system being identified in the greater amounts in the brain cortex, basal ganglia, spinal cord, cerebellum, hippocampus and olfactory areas, owing for the modulatory action of ECS on cognitive function, memory, behaviour, emotion and locomotor activity. Their location in the periaqueductal grey matter and dorsal spinal cord may explain their involvement in pain sensation and modulation. Colocallization of the CB1 receptors with the oroxinergic projection system in the lateral hypothalamus is responsible for their implication in feeding behaviour. CB2 receptors were found in the cells of immune system (spleen, macrophages). It should be noted that ECS may also play a role in the regulation of fertility and pre-and postnatal development. The stimulation of ECS receptors is associated with the activation of MAPK, PI/PKB and MEK/ERK signalling pathways with increased activity of different transcription factors. CB1 receptors are involved in neuronal exitability by decreasing synaptic input, implying retrograde transmission and presynaptic inhibition resulting in reduction of neurotransmitter release. In the article it is also described an ionic mechanisms of release of ECS and the steps of their synthesis as well as participation of a transporter in ECS uptaken process in neurons and astrocytes. Aside from this it is proposed the mechanisms of analgesic action of ECS especially concerning reduction in neuropathic pain in comparison to opioids and possible involvement of α2-adrenoceptors in antinociceptive activity of ECS. Some analgesic properties of ECS is due to their inhibitory action on cyclooxygenase-2 (COX-2). Recent evidences showed that regarding antinociceptive action of ECS along with CB1 receptors most significant receptors are PPAR-alpha and TRPV receptors. There are controversial data concerning the influence of ECS on cognitive function. Knockout mices with the absence of CB1 receptors have showed improved memory and long-term potentiation proofing the significant role of ECS in the disorders of "old memories". Some data suggests that genetic or pharmacological inhibition of COX-2 activity may reduce disorders in hippocampal long-term synaptic plasticity and fear memory, as well as supports improving effects of tetrahydrocannabinoids (THC) on neurodegenerative processes such as Alzheimer's disease, because THC facilitates to marked expression of an important endopeptidase neprilysin for degradation of AB proteins. A number of evidence indicates the possible involvement of ECS in schizophrenia and major depressive disorders. Assumingly such beneficial effect of ECS is associated with M1/M2 microglial polarization process. In conclusion it is suggested that ECS as natural ligand for their corresponding receptors provide wide spectrum of pharmacological effects may become an interesting targets for future therapeutic intervention.

IMPACT OF FOOD ENRICHED WITH DIETARY FIBER ON PATIENTS WITH CONSTIPATION PREDOMINANT IRRITABLE BOWEL SYNDROME.

The causes of motility disorder of gastrointestinal tract and in particular Irritable Bowel Syndrome IBS are multifold, leading to complexity of treatment and requirement of more precise investigation of different pharmacological and non-pharmacological approaches. The aim of the study was investigation and comparison of the dietary fiber intake among women with constipation-predominant irritable bowel syndrome (IBS-C) and without, improvement of the dietary fiber intake using interventions with less rough changes of food related behavior and study of its effects on the bowel function, general wellbeing and compliance of patients. In total 100 healthy women, without any clinical signs of gastrointestinal disorders and 98 women who met Rome III criteria of IBS-C were enrolled in the dietary fiber intake assessment survey. The dietary habits of all participants, as well as bowel function, digestive feelings and general wellbeing of patients at baseline, on the 7th and 14th day of dietary intervention was assessed by the means of adopted questionnaires. The dietary supplementation was provided during the breakfast with fiber enriched food - bread and muesli. Research data reviled significantly lower daily intake of dietary fiber among patients with IBS-C compared with healthy group. The main source of dietary fiber in IBS-C group was bread and cereals, therefore introduction of dietary fiber rich bread and muesli in the breakfast didn't affect diet-related habits and determined high compliance of patients. Two week long intervention significantly improved the bowel function and irritation related complains, the feeling of general wellbeing was considerably better on the endpoint as well.

[EFFECT OF ACETYLCYSTEINE, CORVITIN AND THEIR COMBINATION ON THE FUNCTIONAL STATE OF LIVER IN RATS WITH PARACETAMOL INDUCED TOXIC HEPATITIS].

Nowadays drug-induced hepatotoxicity is urgent problem worldwide. Currently more than 1000 drugs are hepatotoxic and most often are the reason of acute fulminant hepatitis and hepatocellular failure, the states requiring liver transplantation. The paracetamol induced liver toxicity is related with accumulation of its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is the free radical and enhances peroxidation of lipids, disturbs the energy status and causes death of hepatocytes. During our research we investigated and assessed the efficacy of acetylcysteine, corvitin and their combination in rat model of paracetamol induced acute toxic hepatitis. The study was performed on mature white male Wistar rates with body mass 150-180 g. 50 rats were randomly divided into 5 groups (10 rats in each group). To get the model of acute toxic hepatitis single intraperitoneal injection of paracetamol solution was used (750 mg/kg). Toxic hepatitis was treated with intrapertoneal administration of 40mg/kg acetylcysteine or 100mg/kg corvitin, as well as with combination of these drugs. Monotherapy with acetylcysteine and corvitin of paracetamol induced toxic hepatitis improved the liver function, decreased relative mass of the liver and animal mortality. The treatment of toxic hepatitis was most effective in the case of simultaneous administration of acetylcysteine and corvitin. The normal value of laboratory tests (ALT, ACT, alkaline phosphatase, total and unconjugated bilirubin) was reached and mortality was not more observed. On the bases of obtained data was concluded that acetylcysteine and corvitin have almost equal hepatoprotective activity. The combination of two drugs actually improves the liver function. The most pronounced hepatoprotective effect may be due to synergic action of acetylcysteine and corvitin and such regime can be recommended for correction of liver function.

[ACTION OF L-CARNITINE, CORVITIN AND THEIR COMBINATION ON FUNCTIONAL STATE OF LIVER IN EXPERIMENTAL MODEL OF REYE SYNDROME IN RATS].

Administration of Aacetylsalicylic acid in children with viral infections (influence B, chickenpox) can be related with development of Reye syndrome - severe encephalopathy and liver insufficiency with mortality in 50% of cases. During Reye syndrome most important is deficiency of carnitine and hepatocyte damage. Decreased amount of carnitine impairs the energy function of mitochondria and gluconeogenesis as well as production of urea. As a result develops toxic encephalopathy and liver insufficiency. The goal of the research was assessment of efficacy of L-Carnitine, Corvitin and their combination on functional state of liver in experimental model of Reye Syndrome in rats. The study was performed on mature white male Wistar rates with body mass 150-180g. 50 rats were randomly divided into 5 groups (10 rats in each group). The model of Reye syndrome was induced in accordance with A.Vengersky's method. Intraperitoneal administration of 4-pentenoic acid was performed once daily during seven days, the used dosage was 20mg/kg. The treatment of toxic hepatitis was carried with intraperitoneal administration of L-Carnitine 300mg/kg, Corvitine 100mg/kg and concurrent administration of these drugs. Monotherapy with Corvitin and L-Carnitin successfully improved liver function and equally decreased indicators of hepatocyte's cytolyses and increased levels of glucose and urea. The markers of cholestasis was slightly more improved during use of L-Carnitine. Simultaneous use of both drugs was effective in rats with Reye syndrome, indicators of liver damage normalized and herewith, no mortality outcome was observed. The most pronounced hepatoprotective effect of concurrent administration of L-Carnitine and Corvitin may be due to synergic action of these drugs and such regime can be recommended for correction of liver function during Reye syndrome.

Dietary fiber's benefit for gallstone disease prevention during rapid weight loss in obese patients.

The aim of present study was to compare the effects of very low calorie diets - protein rich and dietary fiber rich food based - on gallstones formation during rapid weight loss. 68 patients were involved into the study. The body weight index in all cases exceeding normal value and equaled to 35±4,7 kg/m2. For weight correction purposes during 5 weeks the patients in first group were kept on a 520-800 kcal diet of "Margi" food products, prepared according our technology, and in the second group on a protein rich diet of the same calorie content. The body weight and changes in the gall-bladder wall and content were assessed by sonography before starting the diet, after three weeks from the commencement of the diet and upon its completion. The measurement of the body weight after completion of the 5 week diet revealed decrease by 10.9±1,5kg in the first group and by 11,2±1,1kg in the second group. Sonography disclosed growth in the amount of biliary sludge in 3 cases in the first group and in 9 cases in the second group. The statistical analyses of results indicate successful and nearly equal reduction of body weight by means of dietary fiber rich and protein rich diet, but high fiber consumption showed statistically significant benefits for prevention of biliary slug accumulation. The study showed that, in the respect to weight loss, diets based on fiber rich and protein rich food are equal, but fiber rich diet has considerable privilege in prevention of gallstone disease. Our findings support the presence of known association between increased dietary fiber consumption and reduction of gallstone formation. Obesity and rapid weight loss are risk factors for development of gallstones. Taking in an account the beneficial effect of dietary fiber, the food rich with this nutrient, particularly low-calorie fiber rich food "Margi", can be recommended for rapid weight loss in obese patients.

Amygdala fMRI lateralizes temporal lobe epilepsy.

OBJECTIVE: To characterize the clinical value of an fMRI task activating the amygdala in controls and patients with mesial temporal lobe epilepsy (MTLE). METHODS: A fearful face fMRI paradigm using video sequences was developed and investigated in 17 patients with epilepsy (12 had MTLE [6 right- and 6 left-sided]) and 17 healthy control subjects. Reproducibility was demonstrated by reimaging 12 of the control subjects. In addition, parahippocampal activation was measured using Roland's Hometown Walking Task within the same session in all patients and in nine of the control subjects. RESULTS: A fearful face paradigm led to significant amygdala activation (p < 0.001) in all subjects. Amygdala activation was bilateral in control subjects and clearly lateralized in patients with MTLE. Dissociated amygdala and parahippocampal activation was found in three MTLE patients. A combination of results from both fMRI paradigms improved the lateralization of the side of seizure onset in patients with MTLE. CONCLUSIONS: fMRI activation of the amygdala evoked by an animated fearful face paradigm is strong, reproducible, and specific in individual subjects. The combination of the fearful face paradigm and Roland's Hometown Walking Task provides a more reliable presurgical mapping of mesial temporal lobe structures.

Bilateral mesial temporal lobe epilepsy: comparison of scalp EEG and hippocampal MRI-T2 relaxometry.

OBJECTIVE: Bilateral hippocampal abnormality is frequent in mesial temporal lobe sclerosis and might affect outcome in epilepsy surgery. The objective of this study was to compare the lateralization of interictal and ictal scalp EEG with MRI T2 relaxometry. MATERIAL AND METHODS: Forty-nine consecutive patients with intractable mesial temporal lobe epilepsy (MTLE) were studied with scalp EEG/video monitoring and MRI T2 relaxometry. RESULTS: Bilateral prolongation of hippocampal T2 time was significantly associated with following bitemporal scalp EEG changes: (i) in ictal EEG left and right temporal EEG seizure onsets in different seizures, or, after regionalized EEG onset, evolution of an independent ictal EEG over the contralateral temporal lobe (left and right temporal asynchronous frequencies or lateralization switch; P = 0.002); (ii) in interictal EEG both left and right temporal interictal slowing (P = 0.007). Bitemporal T2 changes were not, however, associated with bitemporal interictal epileptiform discharges (IED). Lateralization of bilateral asymmetric or unilateral abnormal T2 findings were associated with initial regionalization of the ictal EEG in all but one patient (P < 0.005), with lateralization of IED in all patients (P < 0.005), and with scalp EEG slowing in 28 (82,4%) of 34 patients (P = 0.007). CONCLUSION: Our data suggest that EEG seizure propagation is more closely related to hippocampal T2 abnormalities than IED. Interictal and ictal scalp EEG, including the recognition of ictal propagation patterns, and MRI T2 relaxometry can help to identify patients with bitemporal damage in MTLE. Further studies are needed to estimate the impact of bilateral EEG and MRI abnormal findings on the surgical outcome.

Language lateralization by Wada test and fMRI in 100 patients with epilepsy.

Comparing the determination of language dominance using fMRI with results of the Wada test in 100 patients with different localization-related epilepsies, the authors found 91% concordance between both tests. The overall rate of false categorization by fMRI was 9%, ranging from 3% in left-sided temporal lobe epilepsy (TLE) to 25% in left-sided extratemporal epilepsy. Language fMRI might reduce the necessity of the Wada test for language lateralization, especially in TLE.

Cavernous angioma associated with ipsilateral hippocampal sclerosis.

We report two cases with extratemporal cavernous angioma (CA) and coexisting ipsilateral hippocampal sclerosis. Classically dual pathology is defined as the association of hippocampal sclerosis with an extrahippocampal lesion. Subtle changes in hippocampus might be overlooked in the presence of an unequivocal extrahippocampal abnormality. Seizure outcome after epilepsy surgery in cases with dual pathology is less favourable if only one of the lesions is removed. Dual pathology must always be considered in diagnostic imaging of patients with intractable epilepsy and CA.

Measurement of temporal lobe T2 relaxation times using a routine diagnostic MR imaging protocol in epilepsy.

OBJECTIVE: To determine the applicability of a fast spin-echo (FSE) pulse sequence for T2 relaxation time measurements in diagnostic imaging of temporal lobe epilepsy (TLE) and in epilepsy research. To compare FSE T2-relaxometry to the measurements with multi-echo sequence and visual assessment of MR scans. METHODS: MR imaging and T2 relaxometry was performed with widely used 1.5 T scanner only. Fast dual-echo sequence (TE-14/85 ms) and multi-echo pulse sequence were used for T2 measurements. Normal ranges of T2 values in regions of interest in temporal lobe were estimated in 20 healthy controls. Sixty-five patients with intractable focal epilepsy were studied. Fifty-five patients had TLE, three multilobar focal epilepsy and seven extratemporal focal epilepsy. RESULTS: T2 measurements with the FSE showed good reproducibility in the test objects and control subjects. In one TLE case unilateral focal T2 changes were not identified visually. T2-relaxometry was more sensitive than visual inspection of MR scans in assessing bilateral hippocampal changes: there were 15 cases with abnormal bilateral T2 values. Visually bilateral changes were detected in six out of these 15 cases (40%). In six cases (40%) only unilateral changes were diagnosed visually, and in three cases (20%) bilateral changes were classified as probable with qualitative evaluation. T2 relaxation time measurement supplied additional objective data in cases with ambiguous hippocampal changes on visual assessment: T2-relaxometry confirmed hippocampal abnormalities in seven cases judged visually as probable. In four cases with the suspicion of hippocampal changes T2 values appeared to be normal. CONCLUSION: In TLE patients, images constructed from FSE sequences can be used to estimate T2 relaxation times easily and reliably. T2 measurements are an objective method to diagnose structural changes in the temporal lobe. T2-relaxometry is most helpful to assess bilateral hippocampal abnormalities, and thus might have an impact on estimating postsurgical outcome.

Memory fMRI lateralizes temporal lobe epilepsy.

BACKGROUND: The assessment of mesial temporal lobe (MTL) function is important for the diagnosis and treatment of temporal lobe epilepsy (TLE) and other brain diseases. Declarative memory depends on the integrity of the MTL region. OBJECTIVE: To investigate hemispheric asymmetries of MTL activity in patients with symptomatic TLE. METHODS: With use of blood oxygenation level-dependent fMRI, hemispheric asymmetries in MTL activation of 30 individual patients with refractory symptomatic TLE and 17 healthy control subjects were studied. Activation was induced by a task employing mental navigation and recall of landmarks based on the retrieval of individually familiar visuospatial knowledge. RESULTS: The study demonstrated that the memory task used reliably activated MTL structures in individual control subjects and patients with refractory TLE including children, older subjects, and patients with low formal IQ. Interhemispheric differences in MTL activation lateralized the side of seizure onset in 90% of patients with symptomatic unilateral TLE. In contrast, healthy control subjects did not show a systematic asymmetry of MTL activation. Correlations between MTL activation and neuropsychological measures suggest that the fMRI-detectable MTL changes were specifically related to memory rather than to memory-independent visuospatial abilities. CONCLUSION: fMRI of memory-induced MTL activation lateralizes the side of seizure onset in patients with refractory symptomatic TLE and may provide complementary information for presurgical evaluation.

Carbamazepine reduces memory induced activation of mesial temporal lobe structures: a pharmacological fMRI-study.

BACKGROUND AND PURPOSE: It is not known whether carbamazepine (CBZ; a drug widely used in neurology and psychiatry) influences the blood oxygenation level dependent (BOLD) contrast changes induced by neuronal activation and measured by functional MRI (fMRI). We aimed to investigate the influence of CBZ on memory induced activation of the mesial temporal lobes in patients with symptomatic temporal lobe epilepsy (TLE). MATERIAL AND METHODS: Twenty-one individual patients with refractory symptomatic TLE with different CBZ serum levels and 20 healthy controls were studied using BOLD fMRI. Mesial temporal lobe (MTL) activation was induced by a task that is based on the retrieval of individually familiar visuo-spatial knowledge. The extent of significant MTL fMRI activation was measured and correlated with the CBZ serum level. RESULTS: In TLE patients, the extent of significant fMRI activation over both MTL was negatively correlated to the CBZ serum level (Spearman r = -0.654, P < 0.001). Activation over the supposedly normal MTL, i.e. contralateral to the seizure onset of TLE patients, was smaller than the averaged MTL activation in healthy controls (P < 0.005). Age, duration of epilepsy, side of seizure onset, and intelligence were not correlated to the extent of the significant BOLD-response over both MTL in patients with TLE. CONCLUSIONS: In TLE patients, carbamazepine reduces the fMRI-detectable changes within the mesial temporal lobes as induced by effortful memory retrieval. FMRI appears to be suitable to study the effects of chronic drug treatment in patients with epilepsy.