Animal models to study cognitive impairment of chronic kidney disease.

Mild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD) and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives and society. However, the underlying pathomechanisms are poorly understood and current therapies mostly aim at supporting patients in their daily life. This illustrates the urgent need to elucidate the pathogenesis, and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modelling of cognitive disorders in CKD. We discuss the use of mice, rats and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving therapy of people with CKD and MCI.

Electrocoagulation in treatment of municipal wastewater- life cycle impact assessment.

The purpose of this study is investigation of electrocoagulation (EC) as a treatment of municipal wastewater, integrating life cycle impact assessment (LCIA) for assessing its environmental performance of investigated treatment. The study evaluated the effectiveness of EC in removing physico-chemical and microbial parameters using aluminum (Al) and iron (Fe) electrodes in monopolar and bipolar modes. Bipolar arrangement of Al(-)/Al/Al/Al(+) electrodes achieved the highest removals: 70% COD, 72% BOD5 followed by complete elimination of total phosphorous, turbidity and microbial parameters. This treatment was subject to investigation of the influence of reaction time (t = 10-60 min) on removals at higher current density (CD = 3.33 mA/cm2). In order to reduce energy consumption, the same reaction time range was used with a reduced CD = 2.33 mA/cm2. Following removal efficiencies obtained: 47-72% COD (higher CD) and 53-78% (lower CD); 69-75% BOD5 (higher CD) and 55-74% CD (lower CD); 12-21% NH4- (higher CD) and 7-22% NH4- (lower CD). Total P, NO3- and NO2- compounds showed the same removals regardless the CD. Decrease in current density did not influence removals of total suspended matter, turbidity, salinity as well as microbial parameters. The bipolar arrangement of Al(-)/Al/Al/Al(+) electrodes, assuming a lower CD = 2.33 mA/cm2 and t = 30 min, was assessed with the Recipe 2016Midpoint (H) and USEtox v.2 LCIA methods to explore the environmental justification of using EC for wastewater treatment. The LCIA results revealed that the EC process significantly reduces water eutrophication and toxicity for freshwater and marine ecosystems, but has higher impacts in global warming, fossil fuel consumption, human toxicity, acidification, and terrestrial ecotoxicity due to high energy consumption. This can be mainly explained by the assumption in the study that the EC precipitate is dispersed to agricultural soil without any pre-treatment and material recovery, along with relatively high energy consumption during the process.

Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor.

People living with chronic kidney disease (CKD) frequently suffer from mild cognitive impairment and/or other neurocognitive disorders. This review in two parts will focus on adverse drug reactions resulting in cognitive impairment as a potentially modifiable risk factor in CKD patients. Many patients with CKD have a substantial burden of comorbidities leading to polypharmacy. A recent study found that patients seen by nephrologists were the most complex to treat because of their high number of comorbidities and medications. Due to polypharmacy, these patients may experience a wide range of adverse drug reactions. Along with CKD progression, the accumulation of uremic toxins may lead to blood-brain barrier (BBB) disruption and pharmacokinetic alterations, increasing the risk of adverse reactions affecting the central nervous system (CNS). In patients on dialysis, the excretion of drugs that depend on kidney function is severely reduced such that adverse and toxic levels of a drug or its metabolites may be reached at relatively low doses, unless dosing is adjusted. This first review will discuss how CKD represents a risk factor for adverse drug reactions affecting the CNS via (i) BBB disruption associated with CKD and (ii) the impact of reduced kidney function and dialysis itself on drug pharmacokinetics.

Magnesium suppresses in vivo oxidative stress and ex vivo DNA damage induced by protracted ACTH treatment in rats.

Oxidative stress, arising from disrupted balance between reactive oxygen/nitrogen species (ROS/RNS) and antioxidant defences, has been implicated in the pathogenesis of stress-related disorders. There is a growing body of evidence that supports the relationship between the activity of the hypothalamic-pituitary-adrenal (HPA) stress system, oxidative stress and magnesium (Mg) homeostasis. The present study aimed to explore the gap in our current understanding of antigenotoxic and protective effects of Mg supplementation against excessive ROS production in male rats during chronic treatment with adrenocorticotropic hormone (ACTH). Our findings show that exposure to exogenous ACTH (10 µg/day, s.c., for 21 days), as one of the key mediators of the HPA axis and stress response, produced an increase in superoxide anion levels and a decrease in superoxide dismutase activity in plasma. We observed that Mg supplementation, starting seven days prior to ACTH treatment and lasting 28 days (300 mg/L of drinking water, per os), abolished these effects in experimental animals. Moreover, our study reveals that ACTH increased the susceptibility of peripheral blood lymphocytes to ex vivo H2O2-induced total and high-level oxidative DNA damage, while Mg completely reversed these effects. Collectively, these results highlight the promising role of Mg in stress-related conditions accompanied by increased oxidative stress in animals and support further investigation using human dietary trials.

Corrected evaluation of the breech presentation outcome based on etiology of this presentation in congenitally malformed uterus.

Background: Breech presentation (BP) results from at random filling of the intrauterine cavity, with an equal probability for a BP or cephalic presentation (CP). Each fetus in BP has its "pair" in CP randomly assumed CP. Direct comparison of BP and CP makes bias to less expressed differences between these two groups. It is therefore necessary to subtract the number of fetuses/newborns from the CP set that are identical to the number of fetuses/newborns in the BP set, with identical characteristics, and add this group to the BP set before comparing them to the rest of the CP fetuses/newborns in the matching process. Methods: The procedure encompasses nine variables in pregnancies with a congenitally malformed uterus (CMU) identified at the Department of Obstetrics (1985-2014): gestational age, birth mass, birth length, head circumference, shoulders circumference, umbilical length, placental weight, newborn mass/newborn length ratio, and newborn mass/placental mass ratio. Firstly, the probability of BP was determined and its relation to gestational age, physical characteristics, and previous presentations. Then direct comparison as well as case-control matching of the CP and BP were performed. Case-control matching was based on either a single specific variable (M1) or all combined variables (M2). Findings: 462 deliveries were identified with CMU. In 81 cases of multiparity, a fetal presentation was found to be an independent event regardless of the previous presentation, gestational age, and newborn physical characteristics. In four types of CMU with 337 deliveries (Bicornuate, Didelphys, Unicornuate, Arcuate), 9 variables with 36 instances of comparison were observed. M1 in 10 instances and M2 in 6 instances showed a statistically significant lower value of breech/random presentation compared with CP. CP have lower value in 2 instances in M1 and 1 in M2. Statistically significant differences were absent without the matching process. Interpretations: The study confirms the maximum probability for the BP is 50%. The case-control matching procedure shows that it is able to detect the difference between the breech/random presentation and CP, while the classic method of direct comparison was unable to detect any differences. The outcome of the breech/random presentation in CMU should be evaluated with the described case-control matching procedure.

"Green" nZVI-Biochar as Fenton Catalyst: Perspective of Closing-the-Loop in Wastewater Treatment.

In the framework of wastewater treatment plants, sewage sludge can be directed to biochar production, which when coupled with an external iron source has the potential to be used as a carbon-iron composite material for treating various organic pollutants in advanced oxidation processes. In this research, "green" synthesized nano zero-valent iron (nZVI) supported on sewage sludge-based biochar (BC)-nZVI-BC was used in the Fenton process for the degradation of the recalcitrant organic molecule. In this way, the circular economy principles were supported within wastewater treatment with immediate loop closing; unlike previous papers, where only the water treatment was assessed, the authors proposed a new approach to wastewater treatment, combining solutions for both water and sludge. The following phases were implemented: synthesis and characterization of nano zero-valent iron supported on sewage sludge-based biochar (nZVI-BC); optimization of organic pollutant removal (Reactive Blue 4 as the model pollutant) by nZVI-BC in the Fenton process, using a Definitive Screening Design (DSD) model; reuse of the obtained Fenton sludge, as an additional catalytic material, under previously optimized conditions; and assessment of the exhausted Fenton sludge's ability to be used as a source of nutrients. nZVI-BC was used in the Fenton treatment for the degradation of Reactive Blue 4-a model substance containing a complex and stable anthraquinone structure. The DSD model proposes a high dye-removal efficiency of 95.02% under the following optimal conditions: [RB4] = 50 mg/L, [nZVI] = 200 mg/L, [H2O2] = 10 mM. pH correction was not performed (pH = 3.2). Afterwards, the remaining Fenton sludge, which was thermally treated (named FStreated), was applied as a heterogeneous catalyst under the same optimal conditions with a near-complete organic molecule degradation (99.56% ± 0.15). It could be clearly noticed that the cumulative amount of released nutrients significantly increased with the number of leaching experiments. The highest cumulative amounts of released K, Ca, Mg, Na, and P were therefore observed at the fifth leaching cycle (6.40, 1.66, 1.12, 0.62, 0.48 and 58.2 mg/g, respectively). According to the nutrient release and toxic metal content, FStreated proved to be viable for agricultural applications; these findings illustrated that the "green" synthesis of nZVI-BC not only provides innovative and efficient Fenton catalysts, but also constitutes a novel approach for the utilization of sewage sludge, supporting overall process sustainability.

The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia.

AIMS: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. METHODS: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. RESULTS: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. CONCLUSIONS: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.

Changes in the Behavior and Body Weight of Mature, Adult Male Wistar Han Rats after Reduced Social Grouping and Social Isolation.

Changes in housing density, including individual housing, are commonly necessary in animal research. Obtaining reproducibility and translational validity in biomedical research requires an understanding of how animals adapt to changes in housing density. Existing literature mainly addresses acclimatization after transportation. We used a within-subject design to examine changes in behavior and weight gain of 4-mo-old male Wistar Han rats after reduction of their social group (RSG; due to removal of one rat from a cage containing 3 rats) and social isolation (SI; the removed rat) for the subsequent 2 wk. Changes in weight gain and in exploratory and center-avoidance behavior in an inescapable open arena (OA) were measured before (D0) and on days 7 and 14 (D7 and D14, respectively) after social change. The motor response to d-amphetamine (1.5 mg/kg), which stimulates behavioral arousal in response to novelty, was assessed at D14. Within-subject design revealed that RSG rats in OA had less locomotion at D7 but not more center-avoidance behavior and had returned to the D0 activity level at D14; SI rats in OA had consistently less locomotion and more center-avoidance behavior. Rearing behavior during OA exposure did not change in either group. However, SI rats showed more center-avoidance behavior in OA, greater weight gain, and less amphetamine-induced rearing at D14 as compared with RSG rats. These data indicate that after RSG, mature adult male rats require 2 wk to return to their baseline level of OA-related behavior, while after SI they gain weight and acquire maladaptive exploratory and center-avoidance behavior. The finding that SI produces maladaptive behavioral and physiologic alterations in adult male rats deserves attention because these changes could have confounding effects on research findings.

The Influence of Unlimited Sucrose Intake on Body Weight and Behavior-Findings from a Mouse Model.

A potential relationship between unrestricted sucrose intake (USI), overweight, and emotional/behavioral control has not been well documented. We examined the influence of USI and having less sweetness than expected on body weight (BW), motor/exploratory, anxiety-like, and social dominant behavior in adult C57BL/6J male mice. Animals had free access to water (group 1) or 32% sucrose and water (sucrose groups 2-5) for 10 days. Then, group 2 remained with 32% sucrose while groups 3-5 were subjected to the downshift (24 h access to 4%, 8%, or 16% sucrose). All experimental groups were weighed and tested in the novel-open arena (NA), elevated plus maze (EPM), and tube tests to assess BW, motor/exploratory, anxiety-like, and social dominance behavior, respectively. USI did not influence animals' BW but produced hyperactivity and anxiolytic-like behavior, which was evident in EPM but not in NA; the outcomes of the downshift were comparable. USI did not influence successes/wins in the tube test but altered emotions that drive the winning, favoring a less anxious behavioral phenotype; this was not evident in the downshifted groups. Observed findings suggest that USI promotes sensation-seeking and motivates dominance, without changing BW, while blunted emotional base of social dominance might be an early mark of the downshift.

The influence of continuous prenatal exposure to valproic acid on physical, nociceptive, emotional and psychomotor responses during adolescence in mice: Dose-related effects within sexes.

Clinical findings show that the use of valproic acid (VPA) during pregnancy increases the risk of birth defects and autism spectrum disorder in offspring. Although there is a consensus that monitoring of potential long-term outcomes of VPA exposure is needed, especially in undiagnosed individuals, preclinical studies addressing this issue are rare. The present study examined the effects of continuous intrauterine exposure to a wide dose range of VPA (50, 100, 200, and 400 mg/kg/day) on the physical and behavioral response in peripubertal mice as a rodent model of adolescence. Body weight and the hot plate test [on postnatal days (PND) 25 and 32], the elevated plus-maze test (on PND35), and the open field test (on PND40) served to examine physical growth, the supraspinal reflex response to a painful thermal stimulus and conditional learning, anxiety-like/risk-assessment behavior, as well as novelty-induced psychomotor activity, respectively. VPA exposure produced the following responses: (i) a negative effect on body weight, except for the dose of 100 mg/kg/day in both sexes; (ii) an increase in the percentage of animals that responded to the thermal stimulus above the defined cut-off time interval and the response latency in both sexes; (iii) dose-specific changes within sexes in behavior provoked by a novel anxiogenic environment, i.e., in females less anxiety-like/risk-assessment behavior in response to the lowest exposure dose, and in males more pronounced anxiety-like/risk-assessment behavior after exposure to the highest dose and 100 mg/kg/day; (iv) dose-specific changes within sexes in novelty-induced psychomotor activity, i.e., in females a decrease in stereotypy-like activity along with an increase in rearing, and in males a decrease in stereotypy-like activity only. These findings show that continuous intrauterine exposure to VPA produces maladaptive functioning in different behavioral domains in adolescence and that the consequences are delicate to assess as they are dose-related within sexes.

The Influence of Social Isolation on Social Orientation, Sociability, Social Novelty Preference, and Hippocampal Parvalbumin-Expressing Interneurons in Peripubertal Rats - Understanding the Importance of Meeting Social Needs in Adolescence.

The fulfillment of belonging needs underlies a variety of behaviors. In order to understand how social needs unmet during maturation shape everyday life, we examined social motivation and cognition in peripubertal rats, as a rodent model of adolescence, subjected to social isolation (SI) during early and early-to-mid adolescence. The behavioral correlates of social orientation (social space preference), sociability (preference for social over non-social novelty), and social novelty preference (SNP) were examined in group-housed (GH) and single-housed (SH) rats in a 3-chamber test. The response to social odors was examined to gain insights into the developmental role of social odors in motivated social behavior. Differentiation between appetitive (number of visits/approaches) and consummatory (exploratory time) aspects of motivated social behavior was done to determine which facet of social motivation characterizes maturation when social needs are met and which aspect dominates when social needs are unsatisfied. The SI-sensitive parvalbumin-expressing interneurons (PVI) in the hippocampus were examined using immunohistochemistry. The main findings are the following: (1) in GH rats, the preference for social space is not evident regardless of animals' age, while sociability becomes apparent in mid-adolescence strictly through consummatory behavior, along with complete SNP (appetitive, consummatory); (2) SH promotes staying in a social chamber/space regardless of animals' age and produces an appetitive preference for it only in early-adolescent animals; (3) SH promotes sociability (appetitive, consummatory) regardless of the animals' age and prevents the SNP; (4) the preference for a social odor is displayed in all the groups through consummatory behavior, while appetitive behavior is evident only in SH rats; (5) the response to social odors does not commensurate directly to the response to conspecifics; (6) SH does not influence PVI in the hippocampus, except in the case of early-adolescence when a transient decrease in the dentate gyrus is observed. These results accentuate the developmental complexity of social motivation and cognition, and the power of SI in adolescence to infringe social maturation at different functional levels, promoting appetitive behavior toward peers overall but harming the interest for social novelty. The findings emphasize the importance of the fulfillment of basic social needs in the navigation through the social world.

Brain dysfunction in tubular and tubulointerstitial kidney diseases.

Kidney function has two important elements: glomerular filtration and tubular function (secretion and reabsorption). A persistent decrease in glomerular filtration rate (GFR), with or without proteinuria, is diagnostic of chronic kidney disease (CKD). While glomerular injury or disease is a major cause of CKD and usually associated with proteinuria, predominant tubular injury, with or without tubulointerstitial disease, is typically non-proteinuric. CKD has been linked with cognitive impairment, but it is unclear how much this depends on a decreased GFR, altered tubular function or the presence of proteinuria. Since CKD is often accompanied by tubular and interstitial dysfunction, we explore here for the first time the potential role of the tubular and tubulointerstitial compartments in cognitive dysfunction. To help address this issue we selected a group of primary tubular diseases with preserved GFR in which to review the evidence for any association with brain dysfunction. Cognition, mood, neurosensory and motor disturbances are not well characterized in tubular diseases, possibly because they are subclinical and less prominent than other clinical manifestations. The available literature suggests that brain dysfunction in tubular and tubulointerstitial diseases is usually mild and is more often seen in disorders of water handling. Brain dysfunction may occur when severe electrolyte and water disorders in young children persist over a long period of time before the diagnosis is made. We have chosen Bartter and Gitelman syndromes and nephrogenic diabetes insipidus as examples to highlight this topic. We discuss current published findings, some unanswered questions and propose topics for future research.

Albuminuria as a risk factor for mild cognitive impairment and dementia-what is the evidence?

Kidney dysfunction can profoundly influence many organ systems, and recent evidence suggests a potential role for increased albuminuria in the development of mild cognitive impairment (MCI) or dementia. Epidemiological studies conducted in different populations have demonstrated that the presence of increased albuminuria is associated with a higher relative risk of MCI or dementia both in cross-sectional analyses and in studies with long-term follow-up. The underlying pathophysiological mechanisms of albuminuria's effect are as yet insufficiently studied, with several important knowledge gaps still present in a complex relationship with other MCI and dementia risk factors. Both the kidney and the brain have microvascular similarities that make them sensitive to endothelial dysfunction involving different mechanisms, including oxidative stress and inflammation. The exact substrate of MCI and dementia is still under investigation, however available experimental data indicate that elevated albuminuria and low glomerular filtration rate are associated with significant neuroanatomical declines in hippocampal function and grey matter volume. Thus, albuminuria may be critical in the development of cognitive impairment and its progression to dementia. In this review, we summarize the available evidence on albuminuria's link to MCI and dementia, point to existing gaps in our knowledge and suggest actions to overcome them. The major question of whether interventions that target increased albuminuria could prevent cognitive decline remains unanswered. Our recommendations for future research are aimed at helping to plan clinical trials and to solve the complex conundrum outlined in this review, with the ultimate goal of improving the lives of patients with chronic kidney disease.

Chronic kidney disease and neurological disorders: are uraemic toxins the missing piece of the puzzle?

Chronic kidney disease (CKD) perturbs the crosstalk with others organs, with the interaction between the kidneys and the heart having been studied most intensively. However, a growing body of data indicates that there is an association between kidney dysfunction and disorders of the central nervous system. In epidemiological studies, CKD is associated with a high prevalence of neurological complications, such as cerebrovascular disorders, movement disorders, cognitive impairment and depression. Along with traditional cardiovascular risk factors (such as diabetes, inflammation, hypertension and dyslipidaemia), non-traditional risk factors related to kidney damage (such as uraemic toxins) may predispose patients with CKD to neurological disorders. There is increasing evidence to show that uraemic toxins, for example indoxyl sulphate, have a neurotoxic effect. A better understanding of factors responsible for the elevated prevalence of neurological disorders among patients with CKD might facilitate the development of novel treatments. Here, we review (i) the potential clinical impact of CKD on cerebrovascular and neurological complications, (ii) the mechanisms underlying the uraemic toxins' putative action (based on pre-clinical and clinical research) and (iii) the potential impact of these findings on patient care.

Acidosis, cognitive dysfunction and motor impairments in patients with kidney disease.

Metabolic acidosis, defined as a plasma or serum bicarbonate concentration <22 mmol/L, is a frequent consequence of chronic kidney disease (CKD) and occurs in ~10-30% of patients with advanced stages of CKD. Likewise, in patients with a kidney transplant, prevalence rates of metabolic acidosis range from 20% to 50%. CKD has recently been associated with cognitive dysfunction, including mild cognitive impairment with memory and attention deficits, reduced executive functions and morphological damage detectable with imaging. Also, impaired motor functions and loss of muscle strength are often found in patients with advanced CKD, which in part may be attributed to altered central nervous system (CNS) functions. While the exact mechanisms of how CKD may cause cognitive dysfunction and reduced motor functions are still debated, recent data point towards the possibility that acidosis is one modifiable contributor to cognitive dysfunction. This review summarizes recent evidence for an association between acidosis and cognitive dysfunction in patients with CKD and discusses potential mechanisms by which acidosis may impact CNS functions. The review also identifies important open questions to be answered to improve prevention and therapy of cognitive dysfunction in the setting of metabolic acidosis in patients with CKD.

Specific Changes in the Mammalian Gut Microbiome as a Biomarker for Oxytocin-Induced Behavioral Changes.

Prolonged exposure to psychiatric pharmacological agents is often associated with marked gastrointestinal phenomena, including changes in food intake, bowel motility, gastric emptying, and transit time. Those changes are reflected in the gut microbiota composition of the patient and can, therefore, be objectively measured. This is in contrast to the standard psychiatric evaluation of patients, which includes symptoms that are subjectively assessed (i.e., mood, anxiety level, perception, thought disorders, etc.). The association between a drug's effect on the microbiota and psychiatric symptoms may allow for quantifiable surrogate markers of treatment effectiveness. Changes in the levels of specific drug-sensitive bacterial species can, thus, potentially serve as biomarkers for the intake and effectiveness of psychiatric drugs. Here, we show substantial microbiota changes that were associated with oxytocin administration and the decreased anxiety/depression-like behaviors it conferred in a rat model of corticosterone-induced stress. Compared with oxytocin, citalopram produced more minor effects on the rats' microbiota. Alterations in the gut microbiota may, therefore, reflect the consumption and effectiveness of some psychiatric drugs.

Magnesium enhances cardiomyocyte proliferation and suppresses cardiac fibrosis induced by chronic ACTH exposure in rats.

Chronic stress has been implicated in the development and progression of heart disease. In the past decade, a link between chronic stress and cardiac fibrosis has been described. Here, we focused on investigating the effects of one of the key molecular effectors of the stress response-adrenocorticotropic hormone (ACTH) on cardiac histopathology. More importantly, as the literature data support interplay between magnesium (Mg) and the hypothalamo-pituitary-adrenal (HPA) stress system, we explored potential cardioprotective effects of Mg supplementation in a rat model of ACTH-induced cardiac remodeling. Protracted ACTH exposure in rats resulted in a prominent increase in proliferation of fibroblasts and excessive collagen deposition in the heart, accompanied by enhanced proliferation of cardiomyocytes and vascular endothelial cells. Our results show, for the first time, that administration of Mg in rats was effective in ameliorating the development of ACTH-evoked cardiac fibrosis, while facilitating cardiomyocyte proliferation. Furthermore, we propose that Mg supplementation attenuates ACTH-induced HPA axis hyperactivity, as one of the underlying plausible mechanisms, which may contribute to its cardioprotective effects.

Synergy of oxytocin and citalopram in modulating Itgb3/Chl1 interplay: Relevance to sensitivity to SSRI therapy.

Intranasal treatment with oxytocin showed beneficial effects in post-traumatic stress disorder and autism spectrum disorders; however, it was not investigated as much in depression. Keeping in mind the favorable effects of oxytocin on animal models of anxiety and depression, we postulated that synergy between prescribed first choice drugs, selective serotonin reuptake inhibitors (SSRIs) and oxytocin could improve the treatment outcome compared with SSRI monotherapy. Our previous in vitro genome-wide transcriptomic study on human lymphoblastoid cell lines exposed to paroxetine resulted in increase of integrin ß3 (ITGB3) gene expression, and further, ITGB3/CHL1 expression ratio was hypothesized to influence the sensitivity to SSRIs. The aim of this report was to explore molecular mechanisms behind the antidepressant-like oxytocin effect, alone and in synergy with citalopram, on behavioral and molecular level in corticosterone treated rats, a paradigm used to model anxiety and depression in animals. Oxytocin treatment (1) ameliorated corticosterone-induced reduction of neurogenesis and number of parvalbumin-positive interneurons in the hippocampal CA1 region, (2) enhanced anxiolytic- and antidepressant-like effects of citalopram in the open field test, and (3) the SSRI/oxytocin synergy persisted in reversing the reduction of the Itgb3 gene expression and increased Itgb3/Chl1 ratio in the prefrontal cortices. These results support the existence of synergy between citalopram and oxytocin in reversing the molecular and behavioral changes induced by corticosterone treatment and point to possible molecular mechanisms behind antidepressant-like effect of oxytocin.

Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure: A Systematic Review and Meta-analysis.

Importance: Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization. Objective: To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers. Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions. Study Selection: Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies. Main Outcomes and Measures: Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category. Results: Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies. Conclusions and Relevance: In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.