Maria Bove

Antidepressant drugs for beta amyloid-induced depression: A new standpoint?

ABSTRACT Mounting evidence suggests that depression represents a risk factor and an early manifestation of Alzheimers disease (AD). Neuropsychiatric symptoms may derive from neurobiological changes in specific brain areas and may be considered prodromal of dementia. We have previously reported the depressive‐like profile in rats receiving a single intracerebroventricular injection of soluble amyloid beta protein (ßA). Here, we verified the effect of different classes of antidepressants on the ßA‐induced depressive behavior and on cortical monoamine levels. To these purposes, the forced swimming test was performed and cortical levels of serotonin (5‐HT) and noradrenaline (NA) were quantified by high performance liquid chromatography (HPLC). We found that acute fluoxetine (20 mg/kg, s.c.), reboxetine (10 mg/kg, s.c.), and ketamine (15 mg/kg, i.p.) significantly reduced the immobility in ßA‐treated rats compared to controls. Fluoxetine and reboxetine reversed 5‐HT reduction, while &bgr;A‐induced NA increase was further enhanced by all treatments. Treatments with fluoxetine, reboxetine and ketamine were able to revert soluble ßA‐induced decrease of cortical BDNF levels, while only fluoxetine and ketamine, but not reboxetine, had the same effects on cortical NGF expression. Moreover, plasma soluble ßA‐levels were lowered by fluoxetine, but not reboxetine and ketamine, treatments. Our data suggest that different classes of antidepressants yield a short‐acting effect on rat soluble ßA‐induced depressive profile. Thus, we hypothesize a novel common mechanism of action of these drugs also based upon a “ßA lowering” effect. Although further investigations are still needed, our study might open a new scenario for unravelling the molecular antidepressant mechanisms of these drugs. HIGHLIGHTSClassical and non‐classical antidepressants revert soluble &bgr;A‐induced depressive phenotype in rats.Fluoxetine reverts soluble &bgr;A‐induced depressive phenotype with a specific “&bgr;A‐lowering” effect.The non‐classical antidepressant ketamine holds neuroprotective properties towards soluble &bgr;A‐induced toxicity.

Visceral Fat Dysfunctions in the Rat Social Isolation Model of Psychosis

Medication with neuroleptics has been associated with adipose tissue dysfunctions and, in particular, with increased visceral fat amount. However, several studies suggested that antipsychotic treatment might not be the main responsible of fat mass accumulation, as this has been also described in not treated psychotic patients. One of the most used “drug-free” rodent models of psychosis is the social isolation rearing of young adult rats, which provides a non-pharmacologic method of inducing long-term alterations reminiscent of symptoms seen in psychotic patients. Recent data highlighted a crucial role of redox imbalance in adipose tissue dysfunctions, in terms of decreased antioxidant defense and increased reactive oxygen species (ROS). Here, we investigated possible oxidative stress-related biomolecular alterations associated with visceral fat increase in 7 week isolated rats. To this purpose, we quantified total and visceral fat amount by using dual-energy X-ray (DEXA) absorptiometry. On visceral fat, we analyzed the expression of specific ROS-producer genes (Nox1, Nox4, Hmox-1), antioxidant enzymes (Prdx1 and Ucp-1) and oxidative stress-induced damage markers (Cidea, Slc2a4, and Acacb). The impact of oxidative stress on beta3-adrenergic receptors (Adrb3), at both mRNA and protein level, was also assessed. We found that 7 weeks of social isolation induced an increase in total and visceral fat, associated with a decrease in Prdx1 (mRNA and protein) as well as Ucp-1 mRNA levels and an enhanced expression of Nox1 (mRNA and protein) and Hmox-1 mRNA. No differences were detected in Nox4 mRNA levels between grouped and isolated animals. Elevations in Cidea, Slc2a4, and Acacb expression in visceral fat of isolated animals accounted for oxidative stress-related damage in this tissue, further associated with a significant increase in Adrb3 mRNA and protein. Our results provide a novel understanding of the pathological link existing among psychosocial stress-induced psychosis, adipose tissue dysfunctions and redox imbalance, opening new therapeutic perspectives for the treatment of alterations in peripheral tissues associated with this mental disorder.

Chlorella sorokiniana Extract Improves Short-Term Memory in Rats

Increasing evidence shows that eukaryotic microalgae and, in particular, the green microalga Chlorella, can be used as natural sources to obtain a whole variety of compounds, such as omega (ω)-3 and ω-6 polyunsatured fatty acids (PUFAs). Although either beneficial or toxic effects of Chlorella sorokiniana have been mainly attributed to its specific ω-3 and ω-6 PUFAs content, the underlying molecular pathways remain to be elucidated yet. Here, we investigate the effects of an acute oral administration of a lipid extract of Chlorella sorokiniana, containing mainly ω-3 and ω-6 PUFAs, on cognitive, emotional and social behaviour in rats, analysing possible underlying neurochemical alterations. Our results showed improved short-term memory in Chlorella sorokiniana-treated rats compared to controls, without any differences in exploratory performance, locomotor activity, anxiety profile and depressive-like behaviour. On the other hand, while the social behaviour of Chlorella sorokiniana-treated animals was significantly decreased, no effects on aggressivity were observed. Neurochemical investigations showed region-specific effects, consisting in an elevation of noradrenaline (NA) and serotonin (5-HT) content in hippocampus, but not in the prefrontal cortex and striatum. In conclusion, our results point towards a beneficial effect of Chlorella sorokiniana extract on short-term memory, but also highlight the need of caution in the use of this natural supplement due to its possible masked toxic effects.

Chronic Psychosocial Stress Impairs Bone Homeostasis: A Study in the Social Isolation Reared Rat

Chronic psychosocial stress is a key player in the onset and aggravation of mental diseases, including psychosis. Although a strong association between this psychiatric condition and other medical co-morbidities has been recently demonstrated, few data on the link between psychosis and bone homeostasis are actually available. The aim of this study was to investigate whether chronic psychosocial stress induced by 4 or 7 weeks of social isolation in drug-naïve male Wistar rats could alter bone homeostasis in terms of bone thickness, mineral density and content, as well as markers of bone formation and resorption (sclerostin, cathepsin K, and CTX-I). We found that bone mineral density was increased in rats exposed to 7 weeks of social isolation, while no differences were detected in bone mineral content and area. Moreover, 7 weeks of social isolation lead to increase of femur thickness with respect to controls, suggesting the development of a hyperostosis condition. Isolated rats showed no changes in sclerostin levels, a marker of bone formation, compared to grouped animals. Conversely, bone resorption markers were significantly altered after 7 weeks of social isolation in terms of decrease in cathepsin K and increase of CTX-I. No alterations were found after 4 weeks of isolation rearing. Our observations suggest that chronic psychosocial stress might affect bone homeostasis, more likely independently from drug treatment. Thus, the social isolation model might help to identify possible new therapeutic targets to treat the burden of chronic psychosocial stress and to attempt alternative therapy choices.

Sub-chronic celecoxib prevents soluble beta amyloid-induced depressive-like behaviour in rats

BACKGROUND Depression and Alzheimers disease (AD) are co-morbid conditions. Neuropsychiatric symptoms have been reported as prodromal symptoms of AD-like dementia and soluble forms of beta amyloid peptide (Aβ), the main constituent of insoluble plaques typical of AD brains, have been implicated in such an effect. We have previously shown that intracerebral injection of Aβ can evoke a depressive-like state in rats, accompanied by neurochemical and neuroendocrine alterations reminiscent of depressive symptoms in humans. AD and depression are crucially linked by neuroinflammation and cyclooxygenase II (COX-2) enzyme involvement is an intriguing field of research. Indeed, its pharmacological inhibition has shown both antidepressant and Aβ modulating effects. METHODS Male rats were exposed to sub-chronic celecoxib (15 mg/kg/day sc for 8 days), a selective COX-2 inhibitor or vehicle (saline), starting from the day before central intracerebroventricular injection of Aβ peptide (5µL of 4 µM solution or vehicle for sham). Animals were tested for depressive-like behaviour by using the forced swimming test paradigm and prefrontal serotonin (5-HT) content and plasma Aβ levels were further evaluated. RESULTS We found that celecoxib treatment prevented the pro-depressive effects induced by Aβ. Moreover, it also prevented the reduction in 5-HT content in prefrontal cortex of Aβ-treated rats and decreased their plasma Aβ levels. CONCLUSIONS Taken together, our data indicate that celecoxib could be a suitable pharmaceutical tool for the treatment of depressive state related to increased Aβ levels.

The Visible Burrow System : A behavioral paradigm to assess sociability and social withdrawal in BTBR and C57BL/6J mice strains

HighlightsThe Visible Burrow System (VBS) is an ethologically valid behavioral paradigm.BTBR mice performed less social behaviors in VBS compared to C57BL/6J strain.BTBR mice had a preference for non‐social behaviors in VBS compared to C57BL/6J mice.BTBR mice showed reduced GABA and increased glutamate levels in specific brain areas. ABSTRACT Disrupted sociability and consequent social withdrawal are (early) symptoms of a wide variety of neuropsychiatric diseases, such as schizophrenia, autism spectrum disorders, depressive disorders and Alzheimer’s disease. The paucity of objective measures to translationally assess social withdrawal characteristics has been an important limitation to study this behavioral phenotype, both in human and rodents. The aim of the present study was to investigate sociability and social withdrawal in rodents using an ethologically valid behavioral paradigm, the Visible Burrow System (VBS). The VBS mimics a natural environment, with male and female rodents housed together in an enclosure where a large open arena is connected to a continuously dark burrow system that includes 4 nest boxes. In this study, mixed‐sex colonies of C57BL/6J and of BTBR mice have been investigated (n = 8 mice per colony). Results showed marked differences between the two strains, in terms of sociability as well as social withdrawal behaviors. In particular, BTBR mice performed less social behaviors and have a preference for non‐social behaviors compared to C57BL/6J mice. Neurobiologically, the decreased sociability of BTBR was accompanied by reduced GABA and increased glutamate concentrations in brain prefrontal cortex (PFC) and amygdala regions. In conclusion, our study validated the use of the VBS as an ethologically relevant behavioral paradigm in group‐housed mice to investigate individual sociability and social withdrawal features and their underlying neurobiology. This paradigm may provide new insights to develop new therapeutic treatments for behavioral dysfunctions that may be relevant across neuropsychiatric diseases.

A long-term treatment with taurine prevents cardiac dysfunction in mdx mice

&NA; Taurine is an amino acid abundantly present in heart and skeletal muscle. Duchenne muscular dystrophy (DMD) is a genetic disorder in which the absence of dystrophin leads to skeletal muscle wasting and heart failure. An altered taurine metabolism has been described in dystrophic animals and short‐term taurine administration exerts promising amelioration of early muscular alterations in the mdx mouse model of DMD. To reinforce the therapeutic and nutraceutical taurine potential in DMD, we evaluated the effects of a long‐term treatment on cardiac and skeletal muscle function of mdx mice in a later disease stage. Taurine was administered in drinking water (1 g/kg/day) to wt and mdx mice for 6 months, starting at 6 months of age. Ultrasonography evaluation of heart and hind limb was performed, in parallel with in vivo and ex vivo functional tests and biochemical, histological and gene expression analyses. 12‐month‐old mdx mice showed a significant worsening of left ventricular function parameters (shortening fraction, ejection fraction, stroke volume), which were significantly counteracted by the taurine treatment. In parallel, histologic signs of damage were reduced by taurine along with the expression of proinflammatory myocardial IL‐6. Interestingly, no effects were observed on hind limb volume and percentage of vascularization or on in vivo and ex vivo muscle functional parameters, suggesting a tissue‐specific action of taurine in relation to the disease phase. A trend toward increase in taurine was found in heart and quadriceps from treated animals, paralleled by a slight decrease in mdx mice plasma. Our study provides evidences that taurine can prevent late heart dysfunction in mdx mice, further corroborating the interest on this amino acid toward clinical trials.

Studying social withdrawal in group housed mice using semi-natural conditions

Background Currently, neuropsychiatric disorders are separated by convention based clustering of qualitative symptoms, not underlying aetiology. This methodology might be sufficient for general clinical management, but it disregards neurobiology. A better understanding of the neurobiology and the application of this knowledge will lead to enhanced treatment efficacy and would provide patients with improved understanding of their condition. A first step in linking nosology to neuroscience is showing how neuropsychiatric symptoms can be measured by quantitative biological parameters and, how these quantitative biological parameters are shaped by neurobiological processes. For example, Schizophrenia, Alzheimer’s disease, Major Depressive disorder and autism spectrum disorder have one overlapping symptom, social withdrawal [1]. This suggests that neurobiological mechanisms might overlap. Thus, scrutinizing the characteristics of this behavioural deficit could elucidate mechanisms relevant for multiple neuropsychiatric disorders. Animal studies are essential in this endeavour, as behaviour and the underlying mechanisms can be examined in more detail. However, efforts are needed to establish the definition and assessment tools for social withdrawal that is relevant beyond the diagnostic boundaries. In earlier studies, the focus has primarily been on scrutinizing social withdrawal in a dyadic interaction, in which a single animals can engage in social behaviour with a single other (e.g., [2]). This, however, does not allow for the natural behavioural potential, such as the natural burrowing behaviour of these animals. Studying social behaviour in a semi-natural environment would allow for a translational setting in which the full range of behaviours can be explored. This study proposes the visible burrow system (VBS) for this purpose. This system consists of an open arena and a burrow with separate nests, from which the latter is exposed to constant darkness. Mimicking the natural setting, this system allows rodents to display natural behaviours and withdraw into one of the nests. Aim This study aims to explore the full behavioural range of the BTBR mouse, a mouse line showing aberrant social behaviours, in a semi-natural VBS environment to study social withdrawal. Furthermore we aim to connect this to GABA, which has been shown to play a key role in social behaviour [3]. Method In assessing the full range of behavioural deficits accompanying social withdrawal, BTBR and C57BL/6J reference mice are placed in the VBS. Colonies of 8 mice (6 males and 2 females) are exposed to the VBS for five consecutive days after which animals are sacrificed and brains are extracted for GABA measurement by mean of HPLC. Statistical analyses is performed by means of ANOVA (longitudinal) and Student’s T-test (week means), comparing BTBR with C57Bl/6j mice (α=0.05). Results/Conclusion In accordance with previous data [4], BTBR mice showed a significant decrease in social behaviours and an increase in non-social behaviour. This coincided with a reduction of GABA in both the prefrontal cortex and the amygdala. Taken together, these data suggests the VBS as a tool for studying translation behavioural characteristics regarding social withdrawal and its neurochemical correlates.

Effects of n-3 PUFA enriched and n-3 PUFA deficient diets in naïve and Aβ-treated female rats

Graphical abstract Figure. No caption available. &NA; Depression is one of the most common psychiatric diseases and the prevalence of depressive symptoms in women is almost twice compared to men, although the reasons of this gender difference are not fully understood yet. Recently, soluble A&bgr;1–42 peptide has been receiving great importance in the development of depression, also since depression is highly comorbid with Alzheimers disease and other neurodegenerative illnesses. Accordingly, we have previously shown that central A&bgr; injection is able to elicit depressive‐like phenotype in male rats. In the present study, we reproduced for the first time the A&bgr;‐induced depressive‐like model in female rats, evaluating behavioural and neurochemical outcomes. Moreover, we studied the effect of lifelong exposure to either n‐3 PUFA enriched or n‐3 PUFA deficient diet, in female rats, both intact and after central A&bgr; administration. Our results confirmed the A&bgr;‐induced depressive‐like profile also in female rats. Moreover, chronic exposure to n‐3 PUFA deficient diet led to highly negative alterations in behavioural and neurochemical parameters, while lifelong exposure to n‐3 PUFA enriched diet was able to restore the A&bgr;‐induced depressive‐like profile in female rats. In conclusion, the A&bgr;‐induced depressive‐like profile was reversed by n‐3 PUFA supplementation, indicating a possible therapeutic role of n‐3 PUFA in the treatment of the burden of depressive disorders.