Ewa Szczęsny

A new animal model of (chronic) depression induced by repeated and intermittent lipopolysaccharide administration for 4 months

Chronic activation of immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways plays an important role in the pathophysiology of clinical depression. Increased IgA responses directed against LPS of gram-negative bacteria, indicating increased bacterial translocation, may be one of the drivers underpinning these pathways. There is a strong association between signs of bacterial translocation and chronicity of depression and O&NS, but not pro-inflammatory cytokines. The aims of the present study were to: (1) develop a new neurobehavioral model of (chronic) depression (anhedonic behavior) that may reflect chronic LPS stimulation and is associated with increased oxidative stress, and (2) to delineate the effects of fluoxetine on this new depression model. We established that in female mice repeated LPS injections once daily for 5 days (from 750 μg/kg to a maximal dose 1250 μg/kg; increasing doses for the first three days which were then gradually decreased on day 4 and 5) at a one-month interval and this repeated for 4 consecutive months induced chronic anhedonia (estimated by the preference to drink a 1% sucrose) lasting for at least 7 weeks. Chronic LPS administration significantly decreased thymus weight, proliferative activity of splenocytes, production of interferon (IFN)γ and interleukin-(IL)10, and increased superoxide and corticosterone production. Treatment with fluoxetine for 3 weeks abolished the neurobehavioral effects of LPS. The antidepressant effect of fluoxetine was accompanied by increased production of IL-10 and reduced superoxide and corticosterone production. Our results suggest that repeated intermittent LPS injections to female mice may be a useful model of chronic depression and in particular for the depressogenic effects of long standing activation of the toll-like receptor IV complex.

Maternal immune activation leads to age-related behavioral and immunological changes in male rat offspring - the effect of antipsychotic drugs

BACKGROUND Prenatal immune system disturbances have been postulated to play an important role in pathogenesis of schizophrenia and related disorders. In the present study, we sought to answer the question whether behavioral changes in the neurodevelopmental model of schizophrenia in rats are accompanied by alterations in proliferative activity of splenocytes and pro- and anti-inflammatory cytokine levels. Furthermore, the effects of two antipsychotic drugs on these parameters were determined. METHODS Lipopolysaccharide (LPS) was administered subcutaneously to pregnant dams at a dose of 1 mg/kg every second day from the 7(th) day of pregnancy till delivery. Age-dependent behavioral and immunological changes were studied when control and prenatally LPS-pretreated offspring male rats were 30 and 90 days old. Chlorpromazine (10 mg/kg ip) or clozapine (10 mg/kg ip) was administered chronically (21 days) after behavioral verification to 3 months old offspring males. Changes in sensorimotor gating (prepulse inhibition, PPI), mitogen-induced proliferative activity of splenocytes ([(3)H]-thymidine incorporation) and cytokine levels (ELISA) were measured. RESULTS Prenatally LPS-pretreated rats showed PPI deficit only at 90 but not at 30 days of age, whereas an enhancement of mitogen-stimulated proliferative activity of splenocytes was observed in both time points. Additionally, the level of proinflammatory cytokines (IL-1β, IL-2, IL-6, TNF-α) in prenatally LPS-pretreated rats was enhanced when they were 30 days old and remained elevated in 90 days old offspring. No changes in IL-10 level were observed. Chronic administration of chlorpromazine or clozapine reduced the deficit in PPI deficit in prenatally LPS-treated rats. In the used model, chlorpromazine normalized both T and B lymphocyte proliferation, whereas clozapine B lymphocyte activity only. Moreover, both antipsychotics modulated the enhanced levels of IL-1β, IL-2 and TNF-α in the offspring of LPS-treated mothers. CONCLUSIONS This study indicates that in LPS-evoked model of schizophrenia, peripheral immunological changes are long-lasting and precede behavioral deficit. The disturbances in T cell-mediated immunity as well as cytokine production were attenuated by antipsychotic drug administration.

The impact of prenatal stress on insulin-like growth factor-1 and pro-inflammatory cytokine expression in the brains of adult male rats: The possible role of suppressors of cytokine signaling proteins

Stress, inflammation and the reduced expression of neurotrophic factors are risk factors for depression. The objective of this study was to determine if prenatal stress affects IGF-1 - cytokine interactions by influencing suppressors of cytokine signaling (SOCS) in the brains of adult rats, in basal conditions and after acute lipopolysaccharide (LPS) treatment. We demonstrated that prenatal stress leads to depression-like behavior, decreased IGF-1, increased IL-1β, TNF-α and IFN-γ release and disturbed SOCS-1, SOCS-2 and SOCS-3 expression in the hippocampus and frontal cortex of adult offspring. Furthermore, prenatal stress enhances the brain response to LPS-evoked inflammatory challenges.

Possible contribution of IGF-1 to depressive disorder

Depression is an illness of unknown origin and involves the dysregulation of many physiological processes disturbed in this disease. It has been postulated that the pathomechanism of depression is complex, and apart from changes in neurotransmitters, a dysregulation of the immune and endocrine systems also plays an important role in the development of this disorder. Recent studies indicate that an impairment of synaptic plasticity in specific areas of the central nervous system (CNS), particularly the hippocampus, may be an important factor in the pathogenesis of depression. The abnormal neural plasticity may be related to alterations in the levels of neurotrophic factors. On this basis, a theory connecting the occurrence of depression with disturbances in neurotrophic factors has gained great attention. This review summarizes data suggesting a role for the neurotrophic factors - especially insulin-like-growth factor-1 (IGF-1) - as possible targets for therapy in depression in the context of depressive behavior modulation, anti-inflammatory action and neuroprotection.

Prenatal stress affects insulin-like growth factor-1 (IGF-1) level and IGF-1 receptor phosphorylation in the brain of adult rats

It has been shown that stressful events occurring in early life have a powerful influence on the development of the central nervous system. Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation and survival of both neurons and glial cells and is thought to exert antidepressant-like activity. Thus, it is possible that disturbances in the function of the IGF-1 system may be responsible for disturbances observed over the course of depression. Prenatal stress was used as a valid model of depression. Adult male offspring of control and stressed rat dams were subjected to behavioural testing (forced swim test). The level of IGF-1 in the blood and the expression of IGF-1, IGF-1R, and IRS-1/2 in the hippocampus and frontal cortex using RT-PCR, ELISA and western blotting were measured. In addition the effect of intracerebroventricularly administered IGF-1 and/or the IGF-1R receptor antagonist JB1 in the forced swim test was studied. Prenatally stressed rats showed depressive like behaviour, including increased immobility time as well as decreased mobility and climbing. Intracerebroventricular administration of IGF-1 reversed these effects in stressed animals, whereas concomitant administration of the IGF-1R antagonist JB1 completely blocked the effects. Biochemical analysis of homogenates from the hippocampus and frontal cortex revealed decreases in IGF-1 level and IGF-1R phosphorylation along with disturbances in IRS-1 phosphorylation. These findings reveal that prenatal stress alters IGF-1 signalling, which may contribute to the behavioural changes observed in depression.

Prenatal stress leads to changes in IGF-1 binding proteins network in the hippocampus and frontal cortex of adult male rat.

Depression is a mental disorder of still unknown origin. Currently, much attention is paid to the potential influence of disturbances in the functioning of neurotrophic factors on the onset of this disease. Insulin-like growth factor 1 (IGF-1) is one of the most important growth agents affecting processes that are crucial for brain development. To date, there are no data showing the impact of prenatal stress on the family of six IGF binding proteins (IGFBP 1-6) that regulate IGF-1 bioactivity. The goal of this study was to investigate whether the decreased expression of IGF-1 in the frontal cortex (FCx) and hippocampus (Hp) of adult male rats following a prenatal stress procedure is related to changes in the IGFBP family. Our results show that rats exposed prenatally to stressful stimuli displayed depression-like behavior based on sucrose preference and elevated plus maze tests. In both cases, in the adult rat brain structures that were examined after the prenatal stress procedure, the IGF-1 protein level was reduced. Moreover, we observed changes of varying degrees in the levels of IGFBPs in stressed animals. A decrease in IGFBP-2 and IGFBP-3 accompanied by an increase in the IGFBP-4 concentration in the Hp and the FCx was detected. There were no differences in IGFBP-1 and IGFBP-6 brain levels between the stressed and control animals, whereas IGFBP-5 concentration was decreased in the Hp of prenatally stressed animals. This study demonstrated that stress during pregnancy may lead not only to behavioral disturbances but also to a decrease in IGF-1 level and the dysregulation of the IGF-1 binding protein network in adult rat offspring.

Validation of the Polish version of the EORTC QLQ-OV28 module for the assessment of health-related quality of life in women with ovarian cancer

The aim of our study was to undertake a prospective validation study of the Polish version of the EORTC ovarian cancer (EORTC QLQ-OV28) module used together with the EORTC QLQ-C30. The translated module was pilot-tested according to the EORTC guidelines. Patients with histological confirmation of ovarian cancer were eligible for the study. All patients filled out the Polish version of the EORTC QLQ-OV28, the EORTC QLQ-C30 and a demographic questionnaire. Standard validity and reliability analyses were performed. One-hundred and forty patients agreed to take part in the study (mean age ± standard deviation: 63.3 ± 10.2 years). Cronbachs alpha coefficients showed positive internal consistency (0.78–0.91). Interclass correlations for the EORTC QLQ-OV28 ranged from 0.77 to 0.93 and proved appropriate test-retest reliability. Satisfactory convergent and discriminant validity in multi-trait scaling analyses was seen. The Polish version of the EORTC QLQ-OV28 module proved to be a reliable and valid tool for measuring health-related quality of life in patients with ovarian cancer.

Catalase activity in blood fractions of patients with sporadic ALS

BACKGROUND Oxidative stress may be a key element in pathogenesis of sporadic amyotrophic lateral sclerosis (sALS). Several studies proved that markers of peroxidation of lipids, proteins or nucleic acids are increased in postmortem tissue of sALS patients. However, much less is known about enzymatic antioxidant defense mechanism in sALS. OBJECTIVES The aim of the study was to assess catalase (CAT) activity that is implicated in the defense against oxidative stress, in three blood fractions, i.e. erythrocytes, plasma and serum of sALS patients and healthy controls. METHODS Altogether 46 sALS patients and 54 controls were enrolled in the study. CAT activity was estimated using a commercially available assay kit. RESULTS CAT activity in erythrocytes of sALS patients was significantly decreased compared to neurologically healthy controls (p=0.04), whereas CAT activity in plasma and serum was similar in both studied groups. CONCLUSIONS CAT activity in erythrocytes, in contrast to other blood fractions is reduced in sALS cases as compared to controls, which may indirectly indicate that antioxidant defense system in erythrocytes is involved in pathogenesis of sALS.