Effects of the uremic toxin indoxyl sulfate on seizure activity, learning and brain oxidative stress parameters in mice.

Patients with end-stage renal disease often have neurological disorders, with a higher incidence of memory impairment or epilepsy than in the general population. Patients undergoing hemodialysis are particularly exposed to the biological effects of uremic toxins. Indoxyl sulfate (IS) is one of the most potent uremic toxins; however, its possible effects on seizure susceptibility or memory functions have yet to be elucidated. In the current study, we focused on investigating the possible convulsant and amnesic effects of IS in recognized animal models. The study was performed on adult male Swiss mice. IS and scopolamine (SCO) were administered intraperitoneally (i.p.), and pentylenetetrazole (PTZ) was injected subcutaneously (s.c.). All substances were given as single injections. Acute IS administration (400 mg/kg) led to its accumulation in the brain. IS at doses of 200 and 400 mg/kg decreased the PTZ convulsive threshold, and at the same doses, it did not significantly affect the threshold for electroconvulsions. IS (200 and 400 mg/kg) did not impair learning in the passive avoidance test and did not increase the SCO-induced memory impairment in this test. IS increased lipid peroxidation, decreased the level of reduced glutathione, and reduced the activity of superoxide dismutase and catalase in mouse brains. Exposure to IS did not significantly change the activity of acetylcholinesterase in the brain tissue. This study shows that acute exposure to IS induces oxidative stress in the brain and potentiates PTZ-induced seizures in mice. Further studies are needed to find out whether IS-induced oxidative stress may affect epileptic seizures and/or epileptogenesis.

Population Pharmacokinetics and Probability of Target Attainment Analysis of Nadroparin in Different Stages of COVID-19.

BACKGROUND AND OBJECTIVE: The risk of thrombotic complications in critical patients with COVID-19 remains extremely high, and multicenter trials failed to prove a survival benefit of escalated doses of low-molecular-weight heparins (nadroparin calcium) in this group. The aim of this study was to develop a pharmacokinetic model of nadroparin according to different stages of COVID-19 severity. METHODS: Blood samples were obtained from 43 patients with COVID-19 who received nadroparin and were treated with conventional oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation. We recorded clinical, biochemical, and hemodynamic variables during 72 h of treatment. The analyzed data comprised 782 serum nadroparin concentrations and 219 anti-Xa levels. We conducted population nonlinear mixed-effects modeling (NONMEM) and performed Monte Carlo simulations of the probability of target attainment for reaching 0.2-0.5 IU/mL anti-Xa levels in study groups. RESULTS: We successfully developed a one-compartment model to describe the population pharmacokinetics of nadroparin in different stages of COVID-19. The absorption rate constant of nadroparin was 3.8 and 3.2 times lower, concentration clearance was 2.22 and 2.93 times higher, and anti-Xa clearance was 0.87 and 1.1 times higher in mechanically ventilated patients and the extracorporeal membrane oxygenation group compared with patients treated with conventional oxygen, respectively. The newly developed model indicated that 5.900 IU of nadroparin given subcutaneously twice daily in the mechanically ventilated patients led to a similar probability of target attainment of 90% as 5.900 IU of subcutaneous nadroparin given once daily in the group supplemented with conventional oxygen. CONCLUSIONS: Different nadroparin dosing is required for patients undergoing mechanical ventilation and extracorporeal membrane oxygenation to achieve the same targets as those for non-critically ill patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier no. NCT05621915.

Caffeine impairs anticonvulsant effects of levetiracetam in the maximal electroshock seizure threshold test in mice.

OBJECTIVES: Caffeine is the most widely used psychoactive substance in the world. Animal studies indicate that acute caffeine exposure at high doses may induce seizures and diminish the anticonvulsant activity of antiepileptic drugs (AEDs) at much lower doses. The aim of the current study was to assess the effect of caffeine on the anticonvulsant action of levetiracetam (LEV) and vigabatrin (VGB). METHODS: The anticonvulsant activity of LEV and VGB was examined in the maximal electroshock seizure threshold test in mice (MEST test). All drugs were administered intraperitoneally by single injections, and caffeine was applied at doses capable of interfering with AEDs. Effects of caffeine exposure on AEDs were also investigated in tests of memory and motor performance. RESULTS: Caffeine reduced the protective effect of LEV against electroconvulsions. Total brain concentration of LEV was unaffected by caffeine as well as inversely; LEV had no significant impact on the brain caffeine concentration, suggesting a pharmacodynamic nature of the interaction between LEV and caffeine in the MEST test. VGB at applied doses did not affect the convulsive threshold. Administration of VGB, but not LEV, alone or in combination with caffeine, impaired memory retention. In the chimney test, the combined treatment with AEDs and caffeine did not cause motor coordination impairment. CONCLUSIONS: It is suggested that caffeine may negatively affect the anticonvulsant action of LEV in patients with epilepsy.

Endocrine disrupting micropollutants in water and their effects on human fertility and fecundity.

INTRODUCTION AND OBJECTIVE: Micropollutants (MPs) are defined as persistent and biologically-active substances which occur in the environment in trace amounts, mainly as a result of industrial processes and human domestic activity. The published experimental data prove that, among other things, MPs present in the environment may also affect and disturb hormonal balance in humans, resulting in impairment of the reproductive function. In addition to the many MPs disrupting endocrine function described in literature and which exert an effect on human reproductive function, the study presents a review of current literature concerning the exposure to Bisphenol A, phthalates, organochlorine pesticides, and pyrethroids. REVIEW METHODS: Two independent authors searched in PubMed and Google scholar (any date until September 2022) for studies concerning chosen endocrine-disrupting MPs in water and their effects on human fertility and fecundity. BRIEF DESCRIPTION OF THE STATE OF KNOWLEDGE: The review of the literature showed that EDMs present in the environment may create risk in the prenatal and postnatal development following premature birth, and exert a negative effect on fertility and reproductive functions in humans, especially during the perinatal period. SUMMARY: The presented review of literature indicates a negative effect of exposure to BPA, phthalates, OC and OP pesticides, as well as to pyrethroids, regarding human reproductive health. It also demonstrated considerable differences according to gender. Generally, there is a definitely stronger evidence for the presence of a cause-effect relationship between the discussed EDMs and a decreased fertility and fecundity in males. The negative effect of exposure to Bisphenol A, phthalates, selected organochlorine pesticides and pyrethroids appears to be quite well documented.

Influence of Umbelliferone on the Anticonvulsant and Neuroprotective Activity of Selected Antiepileptic Drugs: An In Vivo and In Vitro Study.

Umbelliferone (7-hydroxycoumarin; UMB) is a coumarin with many biological properties, including antiepileptic activity. This study evaluated the effect of UMB on the ability of classical and novel antiepileptic drugs (e.g., lacosamide (LCM), levetiracetam (LEV), phenobarbital (PB) and valproate (VPA)) to prevent seizures evoked by the 6-Hz corneal-stimulation-induced seizure model. The study also evaluated the influence of this coumarin on the neuroprotective properties of these drugs in two in vitro models of neurodegeneration, including trophic stress and excitotoxicity. The results indicate that UMB (100 mg/kg, i.p.) significantly enhanced the anticonvulsant action of PB (p < 0.01) and VPA (p < 0.05), but not that of LCM orLEV, in the 6-Hz test. Whether alone or in combination with other anticonvulsant drugs (at their ED50 values from the 6-Hz test), UMB (100 mg/kg) did not affect motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength; or passive avoidance tests, respectively. Pharmacokinetic characterization revealed that UMB had no impact on total brain concentrations of PB or VPA in mice. The in vitro study indicated that UMB has neuroprotective properties. Administration of UMB (1 µg/mL), together with antiepileptic drugs, mitigated their negative impact on neuronal viability. Under trophic stress (serum deprivation) conditions, UMB enhanced the neurotrophic abilities of all the drugs used. Moreover, this coumarin statistically enhanced the neuroprotective effects of PB (p < 0.05) and VPA (p < 0.001) in the excitotoxicity model of neurodegeneration. The obtained results clearly indicate a positive effect of UMB on the anticonvulsant and neuroprotective properties of the selected drugs.

Effect of caffeine on the anticonvulsant action of pregabalin against electroconvulsions in mice.

BACKGROUND: Experimental data indicate that caffeine (CAF) can reduce the anticonvulsant activity of antiepileptic drugs (AEDs) in animal models of seizures. The purpose of the current study was to examine the effect of CAF on the protective action of pregabalin (PGB) against electroconvulsions in mice. METHODS: Maximal electroshock seizure (MES) test was used in the current study. In addition, the combined treatment with CAF and PGB was assessed in the passive avoidance task (long-term memory) and the chimney test (motor coordination). Drugs were injected intraperitoneally (ip) as single injections. CAF was administered at doses reported to compromise the anticonvulsant action of AEDs in mice. RESULTS: CAF at a dose of 23.1 mg/kg reduced the anticonvulsant action of PGB in the MES test. The brain concentration of PGB was not significantly changed by CAF and vice versa. In the chimney test, CAF (23.1 mg/kg) protected mice against PGB-induced motor coordination impairment. CONCLUSIONS: Regarding seizure control, it might be suggested that patients with epilepsy treated with PGB should avoid taking CAF. The estimated total brain concentration of PGB and CAF does not suggest a pharmacokinetic interaction as an explanation for these results.

Methodology for preparing a cosmetic sample for the development of Microorganism Detection System (SDM) software and artificial intelligence learning to recognize specific microbial species.

INTRODUCTION AND OBJECTIVE: The article presents the methodology of preparing a cosmetic sample for analysi, and the creation of a dataset for teaching artificial intelligence to recognize specific species of microorganisms in cosmetic samples in terms of compliance with the ISO standard document, to develop of the Microorganism Detection System (SDM). MATERIAL AND METHODS: Methodology of preparation a cosmetic sample for testing covers the steps from taking a cosmetic sample to obtaining separated living microorganisms through staining to photos, which in the final stage are used for analysis of the purity of cosmetics by SDM, as well as for learning and testing of the deep convolutional neural network (CNN) for detecting and classifying cells of specific species of bacteria, fungi and yeast in cosmetics, according to the document of standard PN-EN ISO 17516-2014:11. RESULTS: A new techique was devised for preparing a cosmetic sample for the development of Microorganism Detection System (SDM) software, and artificial intelligence learning to recognize specific microbial species. Based on metod demonstrated, the Intelligent algorithms of SDM proved to be effective in counting and recognizing specific microorganisms (average accuracy for Candida albicans - 97%, Escherichia coli - 76%, Pseudomonas aeruginosa - 70%, Staphylococcus aureus - 85%), which are the most important species for the assessment of the purity of cosmetics. In addition, the reproducibility of the developed method was verified, and the results obtained were comparable to the breeding methods currently used, based on specific standards. CONCLUSIONS: The experiments confirmed the high sensitivity and specificity of the SDM method, its repeatability and, above all, the comparability of the results with clasic methods of European standards.

The Microorganism Detection System (SDM) for microbiological control of cosmetic products.

The Microorganism Detection System (SDM) is a new solution using artificial intelligence, unique on the international scale, to correctly identify and count microorganisms, with particular emphasis on specificlisted microorganisms (Document of Standard PN-EN ISO 17516-2014:11) - Candida albicans, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus. SDM enables the use of algorithms for microscopic image interpretation in the microbiological assessment of the cosmetics in accordance with the standard, providing an answer to whether the tested product complies with the standard. Apart from the software part of SDM, an integral part of the system is an innovative methodology for preparing a cosmetic sample for testing. The experiments confirm the high sensitivity and specificity of the SDM method, its repeatability and, above all, the comparability of the results with the methods of European standards.

Assessment of the effect of estradiol on biochemical bone turnover markers among postmenopausal women.

INTRODUCTION: Estrogen deficiency found in postmenopausal women may lead to disturbances in the balance of bone metabolism. Study of the influence of estradiol on markers of bone turnover may help to understand the mechanisms of bone metabolism and to monitor osteoporosis therapy in postmenopausal women at high risk of fractures. The aim of the study was evaluation of the effect of estradiol on the basic markers of bone turnover in postmenopausal women. MATERIAL AND METHODS: The study was conducted in a group of 92 postmenopausal women, divided into two groups: Gr-1 with low estradiol levels ≤ 10 pg/ml and Gr-2 with reference estradiol levels ≥ 25 pg/ml). Basic markers of bone turnover were examined: Ctx (C-terminal cross-linked telopeptide of type I collagen alpha chain) and OC (osteocalcin); pro-resorptive cytokines: IL-6 and TNF-α; vitamin 25(OH)D3 and lipid profile. Women was also analyzed according to demographic and clinical data. RESULTS: A positive relationship was found between estradiol and the main bone formation marker - OC (p = 0.041, r = 0.213) and IL-6, TNF-α (p = 0.007, r = 0.281 and p = 0.018, r = 0.246, respectivly, but only in the group with a reference hormone level. Moreover, the main markers of bone turnover: Ctx and OC showed a mutual positive correlation (p = 0.013; r = 0.257) in women with reference estradiol levels. Relationships between markers of bone remodeling, pro-resorptive cytokines and vitamin D3 depending on the level of estradiol showed no statistically significant correlation. CONCLUSIONS: The study showed that only in women with the reference estradiol level (≥ 25 pg/ml) were the bone formation and resorption processes balanced.

C-11, a New Antiepileptic Drug Candidate: Evaluation of the Physicochemical Properties and Impact on the Protective Action of Selected Antiepileptic Drugs in the Mouse Maximal Electroshock-Induced Seizure Model.

C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM (p < 0.001) and VPA (p < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED50 values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber's rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.

Effect of aliskiren on the anticonvulsant activity of antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice.

Drug-drug interactions should be considered during the pharmacological treatment in patients with epilepsy and coexisting hypertension. Experimental studies in rodents showed that antihypertensive drugs which block the renin-angiotensin system (RAS) are able to decrease seizure severity. The anticonvulsant efficacy of several antiepileptic drugs (AEDs) was enhanced in different seizure models following concomitant treatment with RAS inhibitors. The current study examined the combined treatment with AEDs (carbamazepine, valproate, phenobarbital, clonazepam, ethosuximide, levetiracetam) and aliskiren, the first inhibitor of renin for treating hypertension, in the mouse 6 Hz psychomotor seizure model. The convulsive threshold was not affected by the renin inhibitor up to a dose of 75 mg/kg i.p. However, aliskiren (75 mg/kg) enhanced the anticonvulsant action of valproate reducing its ED50 value from 96.7 to 25.6 mg/kg (P < 0.01). The anticonvulsant potency of other AEDs was unaffected by aliskiren treatment. The combinations of aliskiren with AEDs did not cause adverse effects in mice evaluated in the rota-rod or passive avoidance task. Administration of the renin inhibitor did not significantly alter either plasma or brain concentration of valproate. The obtained results confirm earlier findings from other seizure tests (maximal electroshock and pentylenetetrazole-induced seizure test) that aliskiren has a neutral or positive effect on the anticonvulsant efficacy of AEDs, which suggest its safe use for the treatment of high blood pressure in patients with epilepsy. The beneficial anticonvulsant effect of the concomitant treatment with aliskiren and valproate is worthy of recommendation to further both preclinical and clinical studies.

Nonstationary Pharmacokinetics of Caspofungin in ICU Patients.

Standard dosing of caspofungin in critically ill patients has been reported to result in lower drug exposure, which can lead to subtherapeutic 24-h area under the curve to MIC (AUC0-24/MIC) ratios. The aim of the study was to investigate the population pharmacokinetics of caspofungin in a cohort of 30 intensive care unit patients with a suspected invasive fungal infection, with a large proportion of patients requiring extracorporeal therapies, including extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). Caspofungin was administered as empirical 70 mg antifungal therapy administered intravenously (i.v.) on the first day and at 50 mg i.v. on the consecutive days once daily, and the concentrations were measured after three subsequent doses. Population pharmacokinetic data were analyzed by nonlinear mixed-effects modeling. The pharmacokinetics of caspofungin was described by two-compartment model. A particular drift of the individual clearance (CL) and the volume of distribution of the central compartment (V1) with time was discovered and described by including three separate typical values of CL and V1 in the final model. The typical CL values at days 1, 2, and 3 were 0.563 liters/h (6.7% relative standard error [6.7%RSE]), 0.737 liters/h (6.1%RSE), and 1.01 liters/h (9.1%RSE), respectively. The change in parameters with time was not explained by any of the recorded covariates. Increasing clearance with subsequent doses was associated with a clinically relevant decrease in caspofungin exposure (>20%). The use of ECMO, CRRT, albumin concentration, and other covariates did not significantly affect caspofungin pharmacokinetics. Additional pharmacokinetic studies are urgently required to assess the possible lack of acquiring steady-state and suboptimal concentrations of the drug in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT03399032.).

Effect of aliskiren, a direct renin inhibitor, on the protective action of antiepileptic drugs against pentylenetetrazole-induced clonic seizures in mice.

It has been demonstrated that certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT1 receptor antagonists can possess anticonvulsant activity. The purpose of the current study was to examine the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, against pentylenetetrazole (PTZ)-induced clonic seizures in mice and on the protective activity of conventional antiepileptic drugs (AEDs) in this seizure model. Effects of aliskiren on the PTZ threshold and the protective efficacy of AEDs, such as clonazepam (CLO), phenobarbital (PB), valproate (VPA), and ethosuximide (ETX) in the PTZ test, were evaluated in adult Swiss mice. Aliskiren and AEDs were administered intraperitoneally (i.p.) while PTZ (50-100 mg/kg) was injected subcutaneously (s.c.). The rota-rod and passive avoidance test were used to assess the adverse effects of the combined treatment with aliskiren and AEDs. Aliskiren, at the dose of 75 mg/kg, significantly raised the PTZ threshold (P < 0.05). Furthermore, aliskiren, at the subthreshold dose of 50 mg/kg, significantly enhanced the protective action of CLO (P < 0.01), PB (P < 0.01), and VPA (P < 0.05) but not ETX (P > 0.05) in the s.c. PTZ test. Motor coordination in the rota-rod test and long-term memory in the passive avoidance task were not impaired by the combined treatment of the drugs. This study suggests that treatment with aliskiren can be useful in hypertensive patients with myoclonic seizures. Certainly, a clinical verification of using aliskiren in such patients would be necessary.

Population Pharmacokinetics of High-Dose Tigecycline in Patients with Sepsis or Septic Shock.

Tigecycline is a glycylcycline often used in critically ill patients as the antibiotic of last resort. The pharmacokinetics (PK) of tigecycline in intensive care unit (ICU) patients can be affected by severe pathophysiological changes so that standard dosing might not be adequate. The aim of this study was to describe population PK of high-dose tigecycline in patients with sepsis or septic shock and evaluate the relationship between individual PK parameters and patient covariates. The study population consisted of 37 adult ICU patients receiving a 200-mg loading dose of tigecycline followed by multiple doses of 100 mg every 12 h. Blood samples were collected at 0.5, 2, 4, 8, and 12 h after dose administration. A two-compartment model with interindividual (IIV) and interoccasion (IOV) variability in PK parameters was used to describe the concentration-time course of tigecycline. The estimated values of mean population PK parameters were 22.1 liters/h and 69.4 liters/h for elimination and intercompartmental clearance, respectively, and 162 liters and 87.9 liters for volume of the central and peripheral compartment, respectively. The IIV and IOV in clearance were less than 20%. The estimated values of distribution volumes were different from previously published values, which might be due to pathophysiological changes in ICU patients. No systematic relationship between individual PK parameters and patient covariates was found. The developed model does not show evidence that individual tigecycline dosing adjustment based on patient covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Dosing adjustments should be based on the pathogens, their susceptibility, and PK targets.

Interactions of aliskiren, a direct renin inhibitor, with antiepileptic drugs in the test of maximal electroshock in mice.

Experimental studies showed that certain angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor antagonists can decrease seizure severity in rodents. Additionally, some of these blockers of the renin-angiotensin system have been documented to enhance the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures. The aim of the current study was to investigate the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, on the protective action of numerous antiepileptic drugs (carbamazepine, valproate, clonazepam, phenobarbital, oxcarbazepine, lamotrigine, topiramate and pregabalin) in the test of maximal electroshock in mice. The examined drugs were administered intraperitoneally. Aliskiren up to a dose of 75mg/kg did not affect the threshold for electroconvulsions, however, aliskiren (75mg/kg) enhanced the anticonvulsant action of clonazepam and valproate. Following aliskiren treatment, a higher brain concentration of valproate was noted, suggesting a pharmacokinetic interaction. In the rota-rod test, the concomitant treatment with aliskiren (50 or 75mg/kg) and clonazepam (22.6mg/kg) impaired motor coordination while clonazepam (22.6mg/kg) alone showed strong tendency towards this impairment. The combination of aliskiren (75mg/kg) with phenobarbital (25.5mg/kg) caused long-term memory deficits in the passive avoidance task. This study shows that there are no negative interactions between aliskiren and the examined antiepileptic drugs as concerns their anticonvulsant activity. Aliskiren even potentiated the anticonvulsant action of clonazepam and valproate against maximal electroshock. The impact of aliskiren alone on seizure activity or on the anticonvulsant and adverse activity of antiepileptic drugs needs further evaluation in other animal models of seizures.

Event-related potentials (ERP) and SGIP1 gene polymorphisms in alcoholics: relation to family history of alcoholism and drug usage.

OBJECTIVE: The electrophysiological characteristics may serve as valuable biomarkers for the genetic vulnerability underlying alcoholism. The purpose of this study was to evaluate the potential associations between single nucleotide polymorphisms (SNPs) located in the SGIP1 gene and the theta ERP quantitative traits. METHOD: The theta band (4-7 Hz) visual ERP occurring in the P300 response in the resting EEG were examined to explore the electrophysiological effects of alcohol on the brain in five regions: frontal, central, parietal, temporal and occipital in patients with alcohol addiction. In addition, we tested the potential associations between single nucleotide polymorphisms (SNPs) located in the SGIP1 gene and ERP quantitative traits. RESULTS: We found that the amplitude of the auditory P300 response differed considerably among groups of alcoholics in the frontal, central and temporal areas of the brain and it was lower in the studied brain regions in alcoholics in comparison to non-alcoholics. However, among subjects in the young adult group (GR-1) there was no statistical difference in amplitude of P300 response with control subjects in all studied brain regions in comparison with non-alcoholics. Moreover, we revealed that SNP rs10889635 had a significant effect on P300 amplitude in the central and temporal regions. The reduced P300 amplitude was in AA carriers in comparison to both carriers of GG and GA alleles. CONCLUSION: The present study demonstrated a possible association of target P300 evoked theta and of alcohol dependence with SNPs from the gene SGIP1 in the region of rs10889635, but further studies are required.

Cytotoxicity induced by cypermethrin in Human Neuroblastoma Cell Line SH-SY5Y.

The purpose of this study was to evaluate the cytotoxic potential of Cypermethrin (CM) on cultured human Neuroblastoma SH-SY5Y cells. SH-SY5Y cells were treated with CM at 0-200µM for 24, 48, and 72 h, in vitro. It was found that CM induced the cell death of Neuroblastoma cells in a dose- and time-dependent manner, as shown by LDH assays. Next, some aspects of the process of cell death triggered by CM in the human SH-SY5Y cell line were investigated. It was revealed that the pan-caspase inhibitor Q-VD-OPh, sensitizes SH-SY5Y cells to necroptosis caused by CM. Furthermore, signal transduction inhibitors PD98059, SL-327, SB202190, SP600125 failed to attenuate the effect of the pesticide. Finally, it was shown that inhibition of TNF-a by Pomalidomide (PLD) caused statistically significant reduction in CM-induced cytotoxicity. Overall, the data obtained suggest that CM induces neurotoxicity in SH-SY5Y cells by necroptosis.

Homocysteine, antioxidant vitamins and lipids as biomarkers of neurodegeneration in Alzheimer's disease versus non-Alzheimer's dementia.

INTRODUCTION AND OBJECTIVE: Evidence for the benefit of antioxidants' based therapeutic intervention in dementia are inconsistent. Parallel studies in disease forms of dementia different than Alzheimer's are even less conclusive. In this study, the role of serum levels of homocysteine (tHcy), lipids and antioxidants in predicting the risk of cognitive decline in Alzheimer's disease (AD) versus non-Alzheimer's dementias (n-AD). The objective was to add to the ongoing cumulative research to establish the biochemical baseline for potential nutri-therapeutic intervention in different forms of dementia. MATERIALS AND METHOD: 65 participants with dementia (DP-s) were divided into two groups: ADP--patients with Alzheimer's disease and n-ADP--patients with dementia of a different etiology than primary neurodegenerative dementia in the course of Alzheimer's disease. Cognitive function was assessed by Mini-Mental State Examination (MMSE) and related to plasma levels of tHcy, folate, vitamins B-6, B-12, lipids and vitamins A and E for both groups. Also examined were associations between cognitive impairment and several variables (age, education, duration of dementia) that might confound nutrition-cognition associations. RESULTS: A significant reduction in serum vitamin A levels and elevation of total cholesterol levels were shown for the DP-s group compared to those in the control group. Moreover, significant differences were found in MMSE data and serum vitamin E and tHcy levels between patients with ADP and n-ADP. The scores for MMSE showed a correlation with the vitamin E levels and duration of dementia in the ADP group and/or correlation with tHcy, levels of vitamins A and/or E, and duration of dementia in the n-ADP group. CONCLUSIONS: The results obtained suggest that elevated serum tHcy and decreased levels of vitamins A and E are associated with an increased risk of non-Alzheimer's dementias, although further studies involving a larger cohort are now needed to verify these results.

Cognitive functions, lipid profile, and Apolipoprotein E gene polymorphism in postmenopausal women.

The objective of the study was investigation of the relationship between cognitive functions and lipid profile, BMI and change of body weight in postmenopausal women carriers of Apolipoprotein E gene polymorphisms (APOE). A group of 170 women was recruited to the study. The inclusion criteria were: minimum of two years after the last menstruation, FSH concentration 30 U/ml and no signs of dementia on the Montreal Cognitive Assessment (MoCA). A computerized battery of Central Nervous System Vital Signs (CNS VS) was used for diagnostic cognitive functions. APOE genotype was performed by multiplex PCR. In blood plasma were determined: triglycerides, total cholesterol and its fractions: HDL cholesterol and LDL cholesterol. Statistical analysis was performed using two-way analysis of variance in STATISTICA software. In the postmenopausal women examined, the carrier state of APOE gene polymorphism was associated with the level of triglycerides, and results concerning three cognitive functions: executive functions, psychomotor speed, and cognitive flexibility. Loss of body weight in postmenopausal women was related with lower results in neurocognitive index and the majority of cognitive functions. The results concerning cognitive functions in postmenopausal women in the study were not significantly related with lipid profile. Significant differences were observed according to APOE gene polymorphism in correlations between LDL/HDL and CHOL/HDL ratios, and results in the processing speed and reaction time, as well as between the BMI and results in processing speed in the postmenopausal women examined.

Homocysteine and cognitive disorders of postmenopausal women measured by a battery of computer tests--central nervous system vital signs.

The purpose of the study was the analysis of cognitive functions in postmenopausal women having different status of homocysteine levels by a battery of computer tests-central nervous system vital signs (CNS-VS). We examined whether homocysteine increases the risk of cognitive decline and which cognitive domains are more affected. We showed that the considerably better neurocognitive index was obtained by women with low homocysteine levels in comparison with those with hyperhomocysteinemia (p = 0.0017). Similarly, results were obtained in the field of executive functioning (p = 0.0011), complex attention (p = 0.0106), cognitive flexibility (p = 0.0016), and memory (p = 0.0145). Verbal memory and visual memory did not differ considerably among the studied groups. Also, we demonstrated that ε4/ε4 genotype was the most common (15.5 %) in women with hyperhomocysteinemia than in groups of patients with low (0 %) or normal (1.9 %) homocysteine levels. In summary, hyperhomocysteinemia was related with increased risk of decline in executive functioning, complex attention, cognitive flexibility, and memory in postmenopausal women.