Unraveling the Puzzle of Central Serous Chorioretinopathy: Exploring Psychological Factors and Pathophysiological Mechanisms.

Central serous chorioretinopathy (CSCR) is a relatively common retinal disease involving the localized serous detachment of the neurosensory retina from the retinal pigment epithelium (RPE). Research suggests that individuals with a Type A personality, exhibiting traits such as competitiveness, urgency, aggression, and hostility, are significantly more prone to developing CSCR. Several studies have confirmed that a propensity to stress as well as different stressful events may predispose subjects to the development and recurrence of CSCR. Patients with CSCR are more depressive, report a higher level of anxiety and use more psychopharmacologic medications. Despite the research conducted on the topic, it remains unclear how a variety of psychological factors can contribute to dysfunction and pathological changes in the choroid and RPE. Some authors propose that increased levels of sympathetic neurotransmitters and glucocorticoids may alter the choroidal blood flow and increase the permeability of choriocapillaris in CSCR patients. It is generally accepted that hyperpermeable choroidal vessels are responsible for increased tissue hydrostatic pressure, which promotes RPE detachment, breaks the barrier function of the RPE and leads to subretinal fluid accumulation. Although the etiological factors and pathophysiological mechanisms have still not been fully clarified, CSCR is most likely a multifactorial disease involving disturbed interrelationships between biological and psychological factors. This comprehensive review aims to provide an up-to-date exploration of the psychological factors and pathophysiological mechanisms associated with CSCR.

Characterization of the CYP3A4 Enzyme Inhibition Potential of Selected Flavonoids.

Acacetin, apigenin, chrysin, and pinocembrin are flavonoid aglycones found in foods such as parsley, honey, celery, and chamomile tea. Flavonoids can act as substrates and inhibitors of the CYP3A4 enzyme, a heme containing enzyme responsible for the metabolism of one third of drugs on the market. The aim of this study was to investigate the inhibitory effect of selected flavonoids on the CYP3A4 enzyme, the kinetics of inhibition, the possible covalent binding of the inhibitor to the enzyme, and whether flavonoids can act as pseudo-irreversible inhibitors. For the determination of inhibition kinetics, nifedipine oxidation was used as a marker reaction. A hemochromopyridine test was used to assess the possible covalent binding to the heme, and incubation with dialysis was used in order to assess the reversibility of the inhibition. All the tested flavonoids inhibited the CYP3A4 enzyme activity. Chrysin was the most potent inhibitor: IC50 = 2.5 ± 0.6 µM, Ki = 2.4 ± 1.0 µM, kinact = 0.07 ± 0.01 min-1, kinact/Ki = 0.03 min-1 µM-1. Chrysin caused the highest reduction of heme (94.5 ± 0.5% residual concentration). None of the tested flavonoids showed pseudo-irreversible inhibition. Although the inactivation of the CYP3A4 enzyme is caused by interaction with heme, inhibitor-heme adducts could not be trapped. These results indicate that flavonoids have the potential to inhibit the CYP3A4 enzyme and interact with other drugs and medications. However, possible food-drug interactions have to be assessed clinically.

Personality Traits, Stress, and Emotional Intelligence Associated with Central Serous Chorioretinopathy.

BACKGROUND The aim of the present study was to investigate the relationship between personality traits, stress, emotional intelligence, and central serous chorioretinopathy (CSCR). MATERIAL AND METHODS This prospective case-control study included 57 patients with acute CSCR and 57 age- and sex-matched controls with refractive errors. Inclusion criteria for CSCR group were acute unilateral onset of visual disturbances within 2 weeks until the first visit to the ophthalmologist and ophthalmoscopic finding of a round or oval macular detachment confirmed by optical coherence tomography as a dome-shaped serous neuroretinal elevation. RESULTS Using the Sixteen Personality Factor Questionnaire (16 PF), patients with CSCR achieved slightly higher scores on primary characteristics such as warmth (P=0.612) and perfectionism (P=0.137) when compared to the control subjects. Mean scores measured with the Social Readjustment Rating Scale (SRRS) were significantly higher in patients with CSCR (P=0.004), which means that these patients had notably elevated average reactivity to stressful life events. In addition, the number of patients with a high stress level was higher in the CSCR group than in the control group. Considering the level of emotional intelligence measured with the Trait Emotional Intelligence Questionnaire-Short Form (TEIQue-SF), patients with CSCR achieved significantly lower scores on well-being (P=0.003) and sociability (P=0.011) factors, as well as on total score (P=0.014). CONCLUSIONS A higher level of perceived stress is the most important psychological risk factor for CSCR. According to our results, a low level of emotional intelligence may be an additional factor that contributes to the occurrence of CSCR.

Concentrations of Selected Cytokines and Vascular Endothelial Growth Factor in Aqueous Humor and Serum of Diabetic Patients.

Purpose: To investigate the aqueous humor and serum levels of selected cytokines and vascular endothelial growth factor (VEGF) in diabetic patients, implicating their role in the pathogenesis of diabetic eye complications.Materials and methods:   Atotal of 65 patients (27 males and 38 females) who underwent cataract surgery were recruited into the study. The study group consisted of 30 cataract patients with type 2 diabetes mellitus, and this group was divided into two subgroups: 14 patients with diabetic retinopathy (DR group) and 16 patients without DR (NDR group). The control group consisted of 35 non-diabetic cataract subjects.Results: Patients in the DR group had significantly higher aqueous humor concentrations of interleukin (IL)-1ß, IL-6, IL-8, IL-10, monocyte chemotactic protein (MCP-1) and VEGF. Likewise, serum concentrations of IL-1ß, IL-6, IL-8, IL-12, TNF-α and IFN-γ were significantly higher in the DR group as compared to the controls. Aqueous humor concentrations of IL-1ß, IL-8, MCP-1 and VEGF were significantly higher in the DR group as compared with the NDR group.Conclusion: Our findings support the hypothesis that chronic inflammation and a disturbance of the immune system play important roles in the pathogenesis of diabetic cataract and DR.

New Insights into Schizophrenia: a Look at the Eye and Related Structures.

BACKGROUND: Schizophrenia is a multifactorial neurodevelopmental disorder associated with cognitive dysfunction and changes in primary sensory processing. This article aims to explore the current insights into the relationship between schizophrenia and different visual disturbances. METHODS: To provide a literature review of visual impairments in schizophrenia, we performed a PubMed/MEDLINE and Scopus search to identify all articles in English on the topic up to the end of 2018. RESULTS: Multiple retinal functional and structural abnormalities are found in patients with schizophrenia. Wider retinal venules suggest chronically insufficient brain supply of oxygen and this could contribute to the occurrence of psychotic symptoms. Optical coherence tomography studies showed that retinal nerve fiber layer, macular thickness, and macular volume were significantly lowered in the chronic phase of schizophrenia. Results from electroretinogram recordings have demonstrated different declinations such as abnormalities of a - wave activity in the photoreceptors or b - wave activity in the bipolar and Muller cells. Abnormalities in eye movements, such as a notable decrease in saccades and smooth pursuit eye movements, are one of the most reliable and reproducible impairments associated with schizophrenia. Disrupted visual processing of the magnocellular pathway may result in a decrease of contrast sensitivity, sensory processing, orientation discrimination, visual integration, trajectory and spatial localization, backward masking and motion tracking. Visual perceptual abnormalities occur in more than 60% of schizophrenic patients and these are visual hallucinations, perceptual distortion of colors, shapes and light intensity, decrease in contour integration and surround suppression. Other, frequently present eye disorders include impaired visual acuity, strabismus and nystagmus. CONCLUSION: Visual impairments are one of the most important features of schizophrenia, which could help in defining the disease state and assigning appropriate treatment.

LPS-induced inflammation desensitizes hepatocytes to Fas-induced apoptosis through Stat3 activation-The effect can be reversed by ruxolitinib.

Recent studies have established a concept of tumour necrosis factor-α (TNF-α)/Fas signalling crosstalk, highlighting TNF-α as a critical cytokine in sensitizing hepatocytes to death induced by Fas activation. However, in the exact inflammatory response, besides TNF-α, many other mediators, that might modulate apoptotic response differentially, are released. To resolve the issue, we studied the effects of lipopolysaccharide (LPS), one of the crucial inductors of inflammation in the liver, on apoptotic outcome. We show that LPS-induced inflammation diminishes the sensitivity of hepatocytes to Fas stimulus in vivo at caspase-8 level. Analysis of molecular mechanisms revealed an increased expression of various pro-inflammatory cytokines in non-parenchymal liver cells and hepatocyte-specific increase in Bcl-xL, associated with signal transducer and activator of transcription 3 (Stat3) phosphorylation. Pre-treatment with ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, prevented the LPS-induced Stat3 phosphorylation and restored the sensitivity of hepatocytes to Fas-mediated apoptosis. Furthermore, ruxolitinib pre-treatment diminished the LPS-induced Bcl-xL up-regulation without an inhibitory effect on LPS-induced expression of pro-inflammatory cytokines. In summary, although the reports are showing that the effects of isolated pro-inflammatory mediators, such as TNF-α or neutrophils, are pro-apoptotic, the overall effect of inflammatory milieu on hepatocytes in vivo is Stat3-dependent desensitization to Fas-mediated apoptosis.

HEALTH-RELATED QUALITY OF LIFE IN PRIMARY OPEN-ANGLE GLAUCOMA PATIENTS.

The purpose of this research was to evaluate the relationship between general health-related quality of life (GHRQL) and sociodemographic factors in primary open-angle glaucoma (POAG) patients. A prospective cross-sectional study included 207 glaucoma patients. GHRQL was determined via two self-administered questionnaires: the 36-Item Short Form Survey (SF-36) and the EuroQol-5D (EQ-5D) questionnaire. Male and 50- to 69-year-old glaucoma patients, followed by patients who regularly used antiglaucoma therapy and those without progression of glaucoma reported a significantly higher quality of life as measured by the EQ-5D index and the EQ-5D visual analog scale (VAS) (p<0.05 all). Similarly, the Physical Component Summary (PCS) and Mental Component Summary (MCS) of SF-36 had significantly higher values for these patients (p<0.05 all). Furthermore, glaucoma patients with higher education and economic status, glaucoma patients who lived in rural areas, and those who were married achieved higher scores on EQ-5D and SF-36. In conclusion, progression of the disease, female sex, older age, lower education and economic status, urban area and unmarried status negatively affect quality of life in glaucoma patients.

Transient cortical blindness in posterior reversible encephalopathy syndrome after postpartum eclampsia.

Posterior reversible encephalopathy syndrome (PRES) is a clinical condition that can cause different ophthalmological and neurological symptoms. Preeclampsia toxemia or eclampsia is one of the leading causes of PRES. Herein, we present a study of a 35-year old woman who gave birth to healthy twins at 35 weeks of gestation by cesarean section because of threatened preterm delivery. On the 1st postoperative day, the woman developed a severe headache, arterial hypertension, tachycardia, generalized tonic-clonic seizures, and loss of consciousness that persisted for about 2 min. A provisional diagnosis of eclampsia was made, and the woman was then quickly transferred to the intensive care unit where she was treated with antihypertensive therapy, magnesium sulphate, and diazepam. Following stabilization of the general condition, the patient noticed sudden bilateral blindness. An ophthalmological examination revealed significant bilateral loss of vision at the level of insecured light perception, normal pupillary responses to a light stimulus, and normal fundus findings. On this basis, an ophthalmologist made the diagnosis to cortical blindness. Radiographic analysis showed an edematous change in the occipital and parietal brain regions, thus suggesting a diagnosis of PRES. In conclusion, cortical blindness is a clinically striking ophthalmic disorder that may occur in PRES associated with postpartum eclampsia.

Hallucinatory experiences in visually impaired individuals: Charles Bonnet syndrome - implications for research and clinical practice.

BACKGROUND: Charles Bonnet syndrome (CBS) refers to visual hallucinations that occur in individuals with preserved cognitive functions associated with visual impairment. METHODS: This article reviews occurence of visual hallucinations in subjects with CBS by journals published in English in the Pubmed database in the period 1992-2018. Criteria for selection of appropriate papers were sufficient information and perspicuous view on pathogenesis, epidemiology, clinical presentation and treatment possibilities of CBS. RESULTS: Most commonly, visual hallucinations in patients with CBS are complex, repetitive and stereotyped. Such individuals have preserved insight that those percepts are not real, and there is an absence of secondary explanatory delusions and hallucinations within other modalities. Seeing as the aforementioned percepts do not share all the characteristics of hallucinations, it remains unresolved how they should be referred to. Terms as release hallucinations, one that is reflecting its underlying pathogenesis, or confabulatory hallucinatory experiences have been proposed. Moreover, CBS has also been referred to as phantom vision syndrome and may occur in any ophthalmological disease. It is not particularly connected with loss of function along any level of the visual pathway. Although this syndrome is mostly associated with age-related macular degeneration, glaucoma and cataract, it could be related to almost any other ophthalmological conditions. The incidence of CBS alongside with mostly other ocular pathology is rising as population is ageing. CONCLUSIONS: Nonetheless, CBS remains commonly underreported, under recognized and/or misrecognized. Albeit the treatment recommendations and guidelines are not yet fully established, it is important to raise awareness of this specific and distinct condition, which inevitably implicates many differential diagnostic deliberations.

Retinal Layers Measurements following Silicone Oil Tamponade for Retinal Detachment Surgery.

This study aimed to investigate the influence of silicone oil on the retinal nerve fiber layer (RNFL) thickness in patients with primary rhegmatogenous retinal detachment who underwent vitreoretinal surgery. The study included 47 patients (eyes), who underwent a pars plana vitrectomy with the silicone oil tamponade. The control group included unoperated eye of all participants. Spectral-domain optical coherence tomography (SD-OCT) was used for the measurements of peripapilar and macular RNFL thickness. The average peripapillary RNFL thickness was significantly higher in the silicone oil filled eyes during endotamponade and after its removal. The eyes with elevated IOP had less thickening of the RNFL in comparison to the eyes with normal IOP. Central macular thickness and macular volume were decreased in the silicone oil filled eyes in comparison to the control eyes. In conclusion, silicone oil caused peripapilar RNFL thickening in the vitrectomized eyes during endotamponade and after silicone oil removal.

Body Composition and Inflammation in Hemodialysis Patients.

The volume state of dialysis patients is important in guiding the dialysis process. Volume overload in these patients is associated with inflammation. The objectives of the present study were to assess the body composition of patients on hemodialysis; to determine the concentrations of B-type natriuretic peptide (BNP) in plasma and evaluate the association of BNP concentrations with volume overload; to determine the concentrations of C-reactive protein (CRP), albumin and superoxide dismutase (SOD) activities as indicators of inflammatory or antioxidant processes. The study included 79 maintenance hemodialysis patients. Assessment of body compartments was carried out using a body composition monitor (BCM). After BCM measurements, blood samples were taken from the patients for laboratory tests. There were 40 (50.6%) volume-overloaded patients (relative overhydration >15%). These patients had a higher prevalence of arterial hypertension (P < 0.05), significantly higher concentrations of BNP (P = 0.01), lower body mass index (P < 0.05) and lower fat tissue index (P < 0.05). There was a positive correlation between plasma BNP and CRP concentrations (ρ = 0.231; P < 0.05), and a negative correlation between (log) BNP and albumin (r = -0.021; P < 0.05), as well as (log) CRP and albumin concentrations (r = -3; P < 0.01). SOD activity was positively correlated with albumin concentrations (r = 0.254; P < 0.05). The concentrations of BNP in this study were associated with volume overload and inflammatory markers. Patients with a higher albumin concentration had higher SOD activity.

Metabolic risk factors, coping with stress, and psychological well-being in patients with age-related macular degeneration.

The aim of this study was to determine the relationship between the risk factors (age, obesity, hypertension, hyperlipidemia, smoking, consumption of alchohol and drugs, positive family history, and exposure to sunlight), coping with stress, psychological well-being and age-related macular degeneration (ARMD). Forty patients with ARMD (case group) and 63 presbyopes (control group) participated in the study. Patient data were collected through general information questionnaire including patient habits, the COPE questionnaire that showed the way the patients handling stress, and the GHQ that analyzed the psychological aspects of their quality of life. These questionnaires were administered to the patients during ophthalmologic examination. The study involved 46 (44.66%) men and 57 (55.33%) women. Statistical analysis showed that the major risks for the development of ARMD were elevated cholesterol, triglycerides and LDL cholesterol in plasma. A significantly higher number ofARMD patients had a positive family history when compared with presbyopes. This study showed presbyopes to cope with emotional problems significantly better and to have a lower level of social dysfunction when compared with ARMD patients. However, it is necessary to conduct further studies in a large number of patients to determine more accurately the pathophysiological mechanisms of metabolic factors as well as the impact of the disease on the quality of life in patients with ARMD.

Macular thickness after glaucoma filtration surgery.

The aim of present study was to analyze early postoperative changes in the macular area using optical coherence tomography (OCT) after uncomplicated glaucoma filtration surgery. This prospective study included 32 patients (34 eyes) with open-angle glaucoma, which underwent trabeculectomy with or without use of mitomycin C. Exclusion criteria were macular edema, uveitis, age-related macular degeneration, blurred optical media, secondary glaucoma and angle-closure glaucoma. All standard clinical examinations were made before surgery, at the 2nd day, 1 week and 1 month after surgery. Tomography of the macula was performed during every examination using Cirrus HD OCT for the analysis of central subfield thickness. Results show that thickening of the macula was slightly higher 1 week and 1 month after operation in comparison with baseline end 2nd day postoperativelly. There was no significant difference in the change of macular thickness in patients who have used topical prostaglandins compared with those who have used other topical medications. Also, there was no difference in macular changes between patients treated with or without mitomycin C. In conclusion, we found a slight subclinical increase in macular thickness after uncomplicated trabeculectomy, for which we considered that was the result in reduction of intraocular pressure after glaucoma surgery. Macular thickening after glaucoma filtering surgery could be a physiological reaction to the stress of the retina caused by a sudden reduction of intraocular pressure and it is the consequence of altered relationship between capillary pressure and interstitial fluid pressure.

The effect of glucagon and cyclic adenosine monophosphate on acute liver damage induced by acetaminophen.

Recent investigations suggest that glucagon might have a potentially important hepatoprotective activity. We investigated the effect of glucagon in a model of acetaminophen-induced liver injury. CBA male mice were injected intraperitoneally with a lethal (300 mg/kg) or sublethal (150 mg/kg) dose of acetaminophen. The liver injury was assessed by observing the survival of mice, by liver histology and by measuring the concentration of alanine-aminotransferase (ALT). Inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB) protein expressions were determined immunohistochemically. Hepatic levels of reduced glutathione (GSH) and cyclic adenosine monophosphate (cAMP) were also measured. Results show that glucagon, dose and time dependently, protects against acetaminophen-induced hepatotoxicity. This protection was achieved with a dose of 0.5 mg/kg of glucagon given intraperitoneally 15 min before or 1 h after acetaminophen. Treatment of animals with acetaminophen elevated ALT and nitrite/nitrate concentration in the plasma, enhanced iNOS and NF-κB expression and reduced GSH and cAMP concentration in the liver. Animals treated with glucagon had higher hepatic cAMP level, lower ALT and nitrite/nitrate concentration in plasma and lower expression of iNOS in liver cells than animals in control group, whereas there was no difference in the expression of NF-κB. Glucagon did not prevent the loss of GSH content caused by acetaminophen. Our investigation indicates that glucagon has a moderately protective effect against acetaminophen-induced liver injury, which is, at least partially, mediated through the downregulation of iNOS and through the increase in hepatic cAMP content, but it is not mediated through the modulation of NF-κB activity.

Effect of nitric oxide donors S-nitroso-N-acetyl-DL-penicillamine, spermine NONOate and propylamine propylamine NONOate on intracellular pH in cardiomyocytes.

1. Previous studies suggest that exogenous nitric oxide (NO) and NO-dependent signalling pathways modulate intracellular pH (pH(i)) in different cell types, but the role of NO in pH(i) regulation in the heart is poorly understood. Therefore, in the present study we investigated the effect of the NO donors S-nitroso-N-acetyl-DL-penicillamine, spermine NONOate and propylamine propylamine NONOate on pH(i) in rat isolated ventricular myocytes. 2. Cells were isolated from the hearts of adult Wistar rats and pH(i) was monitored using the pH-sensitive fluorescent indicator 5-(and-6)-carboxy seminaphtharhodafluor (SNARF)-1 (10 µmol/L) and a confocal microscope. To test the effect of NO donors on the Na⁺/H⁺ exchanger (NHE), basal pH(i) in Na⁺-free buffer and pH(i) recovery from intracellular acidosis after an ammonium chloride (10 mmol/L) prepulse were monitored. The role of carbonic anhydrase was tested using acetazolamide (50 µmol/L). 4,4-Diisothiocyanatostilbene-2,2'-disulphonic acid (0.5 mmol/L; DIDS) was used to inhibit the Cl⁻/OH⁻ and Cl⁻/HCO3-exchangers. Acetazolamide and DIDS were applied via the superfusion system 1 and 5 min before the NO donors. 3. All three NO donors acutely decreased pH(i) and this effect persisted until the NO donor was removed. In Na⁺-free buffer, the decrease in basal pH(i) was increased, whereas inhibition of carbonic anhydrase and Cl⁻/OH⁻ and Cl⁻/HCO3⁻ exchangers did not alter the effects of the NO donors on pH(i). After an ammonium preload, pH(i) recovery was accelerated in the presence of the NO donors. 4. In conclusion, exogenous NO decreases basal pH(i), leading to increased NHE activity. Carbonic anhydrase and chloride-dependent sarcolemmal HCO3⁻ and OH⁻ transporters are not involved in the NO-induced decrease in pH(i) in rat isolated ventricular myocytes.

Influence of small doses of various drug vehicles on acetaminophen-induced liver injury.

The biological effects of drug vehicles are often overlooked, often leading to artifacts in acetaminophen-induced liver injury assessment. Therefore, we decided to investigate the effect of dimethylsulfoxide, dimethylformamide, propylene glycol, ethanol, and Tween 20 on acetaminophen-induced liver injury. C57BL/6 male mice received a particular drug vehicle (0.6 or 0.2 mL/kg, i.p.) 30 min before acetaminophen administration (300 mg/kg, i.p.). Control mice received vehicle alone. Liver injury was assessed by measuring the concentration of alanine aminotransferase in plasma and observing histopathological changes. The level of reduced glutathione (GSH) was assessed by measuring total nonprotein hepatic sulfhydrils. Dimethylsulfoxide and dimethylformamide (at both doses) almost completely abolished acetaminophen toxicity. The higher dose of propylene glycol (0.6 mL/kg) was markedly protective, but the lower dose (0.2 mL/kg) was only slightly protective. These solvents also reduced acetaminophen-induced GSH depletion. Dimethylformamide was protective when given 2 h before or 1 h after acetaminophen administration, but was ineffective if given 2.5 h after acetaminophen. Ethanol at the higher dose (0.6 mL/kg) was partially protective, whereas ethanol at the lower dose (0.2 mL/kg) as well as Tween 20 at any dose had no influence. None of the vehicles (0.6 mL/kg) was hepatotoxic per se, and none of them was protective in a model of liver injury caused by D-galactosamine and lipopolysaccharide.

The role of prostaglandin E2 in acute acetaminophen hepatotoxicity in mice.

Prostaglandin E2 (PGE2), which is synthesized by many cell types, has a cytoprotective effect in the gastrointestinal tract and in several other tissues and cells. On the other hand, overdose or chronic use of a high dose of acetaminophen (Paracetamol, APAP) is a major cause of acute liver failure in the western world. These observations prompted us to investigate whether PGE2 plays a role in host defence to toxic effect of APAP. (CBAT6T6xC57Bl/6)F1 hybrid mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. Stabile analogue of PGE2, 16,16-dimethyl PGE2 (dmPGE2), or inhibitor of its production, CAY10526, were given intraperitoneally (i.p.) 30 minutes before or 2 hours after APAP administration. The toxicity of APAP was determined by observing the survival of mice during 48 hours, by measuring concentration of alanine-aminotransferase (ALT) in plasma 20-22 hours after APAP administration and by liver histology. The results have shown that PGE2 exhibits a strong hepatoprotective effect when it is given to mice either before or after APAP, while CAY10526 demonstrated mainly the opposite effect. Immunohistochemical or immunofluorescent examinations in the liver tissue generally support these findings, suggesting that PGE2 inhibited APAP-induced activation of nuclear factor kappa B (NF-kappaB). Similarly, PGE2 down regulated the activity of inducible nitric oxide synthase (iNOS), which was up regulated by APAP. Thus, by these and perhaps by other mechanisms, PGE2 contributes to the defence of the organism to noxious effects of xenobiotics on the liver.

The effect of cyclic adenosine monophosphate (cAMP) on acute liver toxicity in mice induced by D-galactosamine and lipopolysaccharide.

The aim of this study was to examine the effect of cyclic adenosine monophosphate (cAMP) and its possible interference/synergism with calcium channel blocker in mice with acute liver injury induced with D-galactosamine (D-GalN) and lipopolysaccharide (LPS). C57Bl/6 mice were given i.p. simultaneously 300 mg/kg D-GalN and LPS 0.01 mg/kg. This treatment induced severe hepatitis, as evidenced by high mortality (80-90%) of control mice and large increase in concentration of aminotransferases in plasma (AST, ALT). Injection of stabile analogue of cAMP (dibutyryl-cAMP, db-cAMP) one hour before hepatotoxic agents increased survival of mice in dose-dependent manner and in medium dose significantly decreased plasma ALT level. Similar (protective) effect had also verapamil, calcium channel blocker, when given in non toxic doses and at the same time schedule as db-cAMP Combination of db-cAMP and verapamil had not synergistic effect in protection from D-GalN+LPS hepatotoxicity; the survival of mice was similar to that seen in protection caused by each agent alone.

The role of prostacyclin in modifying acute hepatotoxicity of acetaminophen in mice.

Prostaglandins (PGs) are lipid compounds that mediate the variety of physiological and pathological functions in almost all body tissues and organs. Prostacyclin (prostaglandin 12, PGI2), which is synthesized by the vascular endothelium, is a potent vasodilator, inhibits the aggregation of platelets in vitro and has cytoprotective effect on gastrointestinal mucosa. The aim of this study was to determine whether PGI2 is playing a role in host defense to toxic effect of acetaminophen (APAP). This was investigated in C57Black/6 mice which were intoxicated with single lethal or high sublethal dose of APAP. APAP was administered to mice by gastric lavage and PGI2 agonists or antagonists were given intraperitoneally (i.p.) 30 minutes before or 2 hours after administration of APAP. The toxicity of APAP was determined by observing the survival of mice during 48 hours, by measuring the concentration of alanine-aminotransferase (ALT) in plasma 20-24 hours after APAP administration, and by liver histology. Mice were given either pure PGI2 (PGI2 sodium salt), its stable agonist (iloprost) or inhibitor of prostacyclin (IP)-receptor (CAY-10441). The results have shown that PGI2 exibits a strong hepatoprotective effect when it was given to mice either before or after APAP (both increase of survival of mice and decrease of plasma ALT levels were statistical significant). Iloprost has not shown a similar effect and CAY-10441 increased toxic effect of APAP if given 2 hours after its administration. Histopathological changes in liver generally support these findings. These investigations support the view that PGI2 is involved in defense of organism to noxious effects of xenobiotics on liver.