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

BACKGROUND: Depression and Alzheimer's 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 (Aß), 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 Aß 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 Aß 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 Aß 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 Aß levels were further evaluated. RESULTS: We found that celecoxib treatment prevented the pro-depressive effects induced by Aß. Moreover, it also prevented the reduction in 5-HT content in prefrontal cortex of Aß-treated rats and decreased their plasma Aß levels. CONCLUSIONS: Taken together, our data indicate that celecoxib could be a suitable pharmaceutical tool for the treatment of depressive state related to increased Aß levels.

N-3 PUFA diet enrichment prevents amyloid beta-induced depressive-like phenotype.

Among neuropsychiatric diseases, depression is one of the most prevalent. Many pathologies have been indicated as comorbid with depression and in particular, neurodegenerative disorders such as Alzheimer's diseases (AD). In this regard, several evidences endorse a strong relationship between depression and AD, so much that this mental illness has been proposed either as a risk factor for AD or as a prodromic AD phase. Furthermore, amyloid beta (Aß) peptide, the main constituent of amyloid plaques commonly considered the principal hallmark of AD brains, has been shown to be increased, in its soluble form, in depressed patients. Accordingly, we have previously found that Aß, intracerebroventricularly (i.c.v.) injected, is able to evoke a depressive-like profile in rats accompanied by low cortical serotonin and reduced neurotrophin content. Taking into account the great increase in AD and depression prevalence, many environmental factors have been under study, particularly dietary factors, and the role of polyunsaturated fatty acids (PUFA) is becoming central in this field of research. Thus, aim of the present study was to evaluate the neurobehavioral effects of lifelong exposure to either n-3 PUFA rich or n-3 PUFA poor diet after Aß central administration. Results showed that n-3 PUFA enriched diet prevented the Aß- induced depressive-like behaviors, as reveled by the reduction in the immobility time in the FST test. Furthermore, n-3 PUFA rich diet exposure reverted also serotonin and neurotrophin level reduction in prefrontal cortex of Aß treated rats. Taken together, our data support the concept that supplementation of diet with n-3 PUFA represents a valid approach to reduce the risk of developing depressive symptoms, as well as reducing the risk of Aß-related pathologies, such as AD.

Low-Dose Aspirin Acetylates Cyclooxygenase-1 in Human Colorectal Mucosa: Implications for the Chemoprevention of Colorectal Cancer.

The mechanism of action of low-dose aspirin in the prevention of colorectal cancer (CRC) remains largely hypothetical. We aimed to compare the effects of low-dose aspirin (100 mg/day for 7 days) given to 40 individuals undergoing CRC screening on the extent of cyclooxygenase (COX)-1 acetylation at serine-529 (AceCOX-1), in blood platelets vs. colorectal mucosa, at 7 (group 1) and 24 h (group 2) after dosing. A significantly (P < 0.01) lower %AceCOX-1 was detected in colonic and rectal mucosa (average 64%) vs. platelets (average 75%) in both groups. This effect was associated with an average 46% (P < 0.01) and 35% (P < 0.05) reduction in prostaglandin (PG) E2 levels and phosphorylated S6 (p-S6) levels, respectively. Rectal mucosal levels of p-S6/S6 significantly (P < 0.01) correlated with PGE2 . These findings demonstrate that low-dose aspirin produces long-lasting acetylation of COX-1 and downregulation of p-S6 in human colorectal mucosa, an effect that may interfere with early colorectal carcinogenesis.

Oxidative-Nitrosative Stress and Myocardial Dysfunctions in Sepsis: Evidence from the Literature and Postmortem Observations.

BACKGROUND: Myocardial depression in sepsis is common, and it is associated with higher mortality. In recent years, the hypothesis that the myocardial dysfunction during sepsis could be mediated by ischemia related to decreased coronary blood flow waned and a complex mechanism was invoked to explain cardiac dysfunction in sepsis. Oxidative stress unbalance is thought to play a critical role in the pathogenesis of cardiac impairment in septic patients. AIM: In this paper, we review the current literature regarding the pathophysiology of cardiac dysfunction in sepsis, focusing on the possible role of oxidative-nitrosative stress unbalance and mitochondria dysfunction. We discuss these mechanisms within the broad scenario of cardiac involvement in sepsis. CONCLUSIONS: Findings from the current literature broaden our understanding of the role of oxidative and nitrosative stress unbalance in the pathophysiology of cardiac dysfunction in sepsis, thus contributing to the establishment of a relationship between these settings and the occurrence of oxidative stress. The complex pathogenesis of septic cardiac failure may explain why, despite the therapeutic strategies, sepsis remains a big clinical challenge for effectively managing the disease to minimize mortality, leading to consideration of the potential therapeutic effects of antioxidant agents.

The NADPH oxidase NOX2 as a novel biomarker for suicidality: evidence from human post mortem brain samples.

Recent evidence points towards a role of oxidative stress in suicidality. However, few studies were carried out on the sources of reactive oxygen species (ROS) in subjects with suicidal behaviour. We have previously demonstrated that the NADPH oxidase NOX2-derived oxidative stress has a major role in the development of neuropathological alterations observed in an animal model of psychosis. Here, we investigated the possible increase in NOX2 in post mortem brain samples of subjects who died by asphyctic suicide (AS) compared with controls (CTRL) and subjects who died by non-suicidal asphyxia (NSA). We found that NOX2 expression was significantly higher in the cortex of AS subjects than in the other two experimental groups. NOX2 immunostaining was mainly detected in GABAergic neurons, with a minor presence of NOX2-positive-stained cells in glutamatergic and dopaminergic neurons, as well as astrocytes and microglia. A sustained increase in the expression of 8-hydroxy-2'-deoxyguanosine, an indirect marker of oxidative stress, was also detected in the cortex of AS subjects, compared with CTRL and NSA subjects. A significant elevation in cortical interleukin-6 immunoreactivity in AS subjects suggested an involvement of cytokine-associated molecular pathways in NOX2 elevations. Our results suggest that the increase in NOX2-derived oxidative stress in the brain might be involved in the neuropathological pathways leading to suicidal behaviour. These results may open innovative insights in the identification of new pathogenetic and necroscopic biomarkers, predictive for suicidality and potentially useful for suicide prevention.

[Fetomaternal transfusion and diagnosis of gestational choriocarcinoma]. / Transfusion materno-fœtale et diagnostic de choriocarcinome gestationnel.

Choriocarcinoma is a rare but agressive malignant trophoblastic neoplasm. Fetomaternal transfusion can be the first sign of choriocarcinoma. We describe two cases of gestational choriocarinoma whose first manifestation was a fetomaternal transfusion. Fetomaternal transfusion is a rare demonstration of choriocarcinoma but its diagnosis must lead to a placenta examination with specific research of choriocarcinoma. The more the therapeutic care is precise, the better is the forecast.

Reactive oxygen species: from health to disease.

Upon reaction with electrons, oxygen is transformed into reactive oxygen species (ROS). It has long been known that ROS can destroy bacteria and destroy human cells, but research in recent decades has highlighted new roles for ROS in health and disease. Indeed, while prolonged exposure to high ROS concentrations may lead to non-specific damage to proteins, lipids, and nucleic acids, low to intermediate ROS concentrations exert their effects rather through regulation of cell signalling cascades. Biological specificity is achieved through the amount, duration, and localisation of ROS production. ROS have crucial roles in normal physiological processes, such as through redox regulation of protein phosphorylation, ion channels, and transcription factors. ROS are also required for biosynthetic processes, including thyroid hormone production and crosslinking of extracellular matrix. There are multiple sources of ROS, including NADPH oxidase enzymes; similarly, there are a large number of ROS-degrading systems. ROS-related disease can be either due to a lack of ROS (e.g., chronic granulomatous disease, certain autoimmune disorders) or a surplus of ROS (e.g., cardiovascular and neurodegenerative diseases). For diseases caused by a surplus of ROS, antioxidant supplementation has proven largely ineffective in clinical studies, most probably because their action is too late, too little, and too non-specific. Specific inhibition of ROS-producing enzymes is an approach more promising of clinical efficacy.

NADPH oxidase elevations in pyramidal neurons drive psychosocial stress-induced neuropathology.

Oxidative stress is thought to be involved in the development of behavioral and histopathological alterations in animal models of psychosis. Here we investigate the causal contribution of reactive oxygen species generation by the phagocyte NADPH oxidase NOX2 to neuropathological alterations in a rat model of chronic psychosocial stress. In rats exposed to social isolation, the earliest neuropathological alterations were signs of oxidative stress and appearance of NOX2. Alterations in behavior, increase in glutamate levels and loss of parvalbumin were detectable after 4 weeks of social isolation. The expression of the NOX2 subunit p47(phox) was markedly increased in pyramidal neurons of isolated rats, but below detection threshold in GABAergic neurons, astrocytes and microglia. Rats with a loss of function mutation in the NOX2 subunit p47(phox) were protected from behavioral and neuropathological alterations induced by social isolation. To test reversibility, we applied the antioxidant/NOX inhibitor apocynin after initiation of social isolation for a time period of 3 weeks. Apocynin reversed behavioral alterations fully when applied after 4 weeks of social isolation, but only partially after 7 weeks. Our results demonstrate that social isolation induces rapid elevations of the NOX2 complex in the brain. Expression of the enzyme complex was strongest in pyramidal neurons and a loss of function mutation prevented neuropathology induced by social isolation. Finally, at least at early stages, pharmacological targeting of NOX2 activity might reverse behavioral alterations.

Extraction, characterization and in vivo neuromodulatory activity of phytosterols from microalga Dunaliella tertiolecta.

In recent years, a great deal of research has been devoted to identify new natural sources of phytosterols and to improve methods for their recovery and purification. In this regard, unexplored natural sources of bioactive ingredients are gaining much attention since they can lead to the isolation of new compounds or bioactivities. The field of available natural sources has been further increased by including algae and, even more interestingly, microalgae. In the present study, a multidisciplinary approach has been used considering, in an integrated view, extraction, chemical composition and bioactivity of phytosterols from the microalga Dunaliella tertiolecta. A novel methodology to extract, separate and characterize microalgal-derived phytosterols has been developed. In addition, recoverable and reusable eluents have been selected in order to reduce the quantities of employed organic solvents. Finally, we addressed the question whether orally administered phytosterols reach the brain and if those interfere with the major neurotransmitter systems, such as the dopaminergic, serotoninergic and noradrenergic ones, in several brain areas of rats. Flash Liquid Chromatography has been used to separate the Total Sterol (TS) fraction, composed of twelve sterols, with a purity of 97.87% and a recovery percentage of 98%, while the "flash version" of Silver Ion Liquid Chromatography has been used to purify the most abundant phytosterols in TS, (22E,24R)- methylcholesta-5,7,22-trien-3ß-ol (ergosterol) and (22E,24R)-ethylcholesta-5,7,22-trien-3ß-ol (7-dehydroporiferasterol), with a purity of 97.4%. These two combined methods did not need sophisticated technologies but only cheap laboratory supplies. Moreover, the possibility of recovering and recycling the solvents used as eluents made it a cleaner process. Finally, for the first time, a neuromodulatory action of Dunaliella tertiolecta-derived phytosterols has been found in selective brain areas of rats.

Estrous cycle affects the neurochemical and neurobehavioral profile of carvacrol-treated female rats.

Carvacrol is the major constituent of essential oils from aromatic plants. It showed antimicrobial, anticancer and antioxidant properties. Although it was approved for food use and included in the chemical flavorings list, no indication on its safety has been estimated. Since the use of plant extracts is relatively high among women, aim of this study was to evaluate carvacrol effects on female physiology and endocrine profiles by using female rats in proestrus and diestrus phases. Serotonin and metabolite tissue content in prefrontal cortex and nucleus accumbens, after carvacrol administration (0.15 and 0.45g/kg p.o.), was measured. Drug effects in behavioral tests for alterations in motor activity, depression, anxiety-related behaviors and endocrine alterations were also investigated. While in proestrus carvacrol reduced serotonin and metabolite levels in both brain areas, no effects were observed in diestrus phase. Only in proestrus phase, carvacrol induced a depressive-like behavior in forced swimming test, without accompanying changes in ambulation. The improvement of performance in FST after subchronic treatment with fluoxetine (20mg/kg) suggested a specific involvement of serotonergic system. No differences were found across the groups with regard to self-grooming behavior. Moreover, in proestrus phase, carvacrol reduced only estradiol levels without binding hypothalamic estradiol receptors. Our study showed an estrous-stage specific effect of carvacrol on depressive behaviors and endocrine parameters, involving serotonergic system. Given the wide carvacrol use not only as feed additive, but also as cosmetic essence and herbal remedy, our results suggest that an accurate investigation on the effects of its chronic exposure is warranted.

Soluble beta amyloid(1-42): a critical player in producing behavioural and biochemical changes evoking depressive-related state?

BACKGROUND AND PURPOSE: Depression is common in early phases of Alzheimer's disease (AD) and may represent prodromal symptoms of dementia. Recent reports suggest that early memory deficits and neuropsychiatric symptoms are caused by soluble rather than aggregated betaamyloid (Abeta). Thus, we investigated the effects of soluble Abeta(1-42) on working memory and depressive/anxiety-related behaviour in rats and on 5-hydroxytryptaminergic neurotransmission and neurotrophin content in various brain regions. EXPERIMENTAL APPROACH: Behavioural reactivity to novel object recognition, open field, elevated plus maze and forced swimming test were assessed 7 days after i.c.v. injection of Abeta(1-42) or its vehicle. BDNF (brain-derived neurotrophic factor) and NGF (nerve growth factor) mRNA and protein levels and 5-hydroxytriptamine (5-HT) content were measured in the prefrontal cortex (PFC), striatum (STR) and nucleus accumbens (NAc). KEY RESULTS: Abeta(1-42) did not affect the ability to distinguish between familiar and novel objects, but Abeta-treated rats exhibited an increase in forced swimming immobility. No differences were revealed between experimental groups in the elevated plus maze test or in self-grooming (evaluated in the open field). In the PFC, but not STR or NAc, Abeta-injected rats exhibited a selective reduction in 5-HT content, BDNF and NGF expression. CONCLUSIONS AND IMPLICATIONS: Our data suggest that soluble Abeta-treated rats have a depressive, but not anxiogenic-like, profile, accompanied by brain region-dependent alterations in the expression of neurotrophins and 5-hydroxytryptaminergic neurotransmission. Hence, these alterations induced by soluble Abeta might be sensitive indicators of early phases of AD and possible risk factors for the expression of neuropsychiatric symptoms in AD.

Soluble amyloid beta1-42 reduces dopamine levels in rat prefrontal cortex: relationship to nitric oxide.

Several studies suggest a pivotal role of amyloid beta (Abeta)(1-42) and nitric oxide (NO) in the pathogenesis of Alzheimer's disease. NO also possess central neuromodulatory properties. To study the soluble Abeta(1-42) effects on dopamine concentrations in rat prefrontal cortex, microdialysis technique was used. We showed that i.c.v. injection or retrodialysis Abeta(1-42) administration reduced basal and K(+)-stimulated dopamine levels, measured 2 and 48 h after peptide administration. Immunofluorescent experiments revealed that after 48 h from i.c.v. injection Abeta(1-42) was no longer detectable in the ventricular space. We then evaluated the role of NO on Abeta(1-42)-induced reduction in dopamine concentrations. Subchronic L-arginine administration decreased basal dopamine levels, measured either 2 h after i.c.v. Abeta(1-42) or on day 2 post-injection, whereas subchronic 7-nitroindazole administration increased basal dopamine concentrations, measured 2 h after i.c.v. Abeta(1-42) injection, and decreased them when measured on day 2 post-Abeta(1-42)-injection. No dopaminergic response activity was observed after K(+) stimulation in all groups. These results suggest that the dopaminergic system seems to be acutely vulnerable to soluble Abeta(1-42) effects. Finally, the opposite role of NO occurring at different phases might be regarded as a possible link between Abeta(1-42)-induced effects and dopaminergic dysfunction.

A 2.6 Mb deletion of 6q24.3-25.1 in a patient with growth failure, cardiac septal defect, thin upperlip and asymmetric dysmorphic ears.

We report a female patient with neurodevelopmental delay and peculiar facial features. She has postnatal growth failure and an atrial septal defect. Patent duct arteriosis and tricuspidal insufficiency were also noted at birth. Characteristic facial features include medial flare eyebrows, dysmorphic helix of the right ear, cupshaped left ear, anteverted nares, long and smooth philtrum, thin upper lip, high vaulted palate. Array-CGH analysis demonstrated the presence of a 2.6 Mb deletion in 6q24.3-25.1. The phenotypic features of this case are very similar to those previously reported in a patient with a 7Mb overlapping deletion, pointing to a specific new syndrome. Twenty-two genes are present in the common critical deleted region. Among them, there is the PPP1R14C gene that encodes for KEPI, a PKC-potentiated inhibitory protein for type-1 Ser/Thr protein phosphatase. Its selective distribution in brain and heart well correlates with developmental delay and cardiac anomalies observed in the patient.

[Acute perforated appendicitis in newborns]. / Appendicite acuta perforata in età neonatale.

The Authors present and discuss a personal case of perforated acute neonatal appendicitis. After a brief review of literature, they delineate the elements that are responsible of rareness of this affection and the causes of frequency of perforation and mortality. Diagnosis is difficult in newborns because clinical and laboratory signs are not specific. They conclude affirming that acute abdomen is an indication for operation even if pre-operating diagnosis of acute neonatal appendicitis is not possible.