From obesity resistance to obesity prediction and prevention?

Comment on: Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction? [Front Neurosci. 2015

The role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of progressive neurodegenerative disease characterized by cognitive impairment and mental disorders. The actual cause and cascade of events in the progression of this pathology is not fully determined. AD is multifaceted in nature and is linked to different multiple mechanisms in the brain. This aspect is related to the lack of efficacious therapies that could slow down or hinder the disease onset/progression. The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway. Recently, the endocannabinoid system emerged as a novel potential therapeutic target to treat AD. In fact, exogenous and endogenous cannabinoids seem to be able to modulate multiple processes in AD, although the mechanisms that are involved are not fully elucidated. This review provides an update of this area. In this review, we recapitulate the role of endocannabinoid signaling in AD and the probable mechanisms through which modulators of the endocannabinoid system provide their effects, thus highlighting how this target might provide more advantages over other therapeutic targets

Modulation of the oxidative stress and lipid peroxidation by endocannabinoids and their lipid analogues

Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes. In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein-coupled receptors 18 and 55. Moreover, the endocannabinoids lipid analogues N-acylethanolamines showed to protect cell damage and death from reactive aldehydes-induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts

L’uso di video tutorial nella formazione di assistenti familiari a domicilio

Il presente contributo descrive un’esperienza di progettazione e realizzazione di video tutorial a supporto dell’apprendimento di assistenti familiari e di persone assistite a domicilio e per l’acquisizione di abilità assistenziali. Il progetto è scaturito da alcune criticità riscontrate da infermieri delle Cure Domiciliari nei percorsi formativi indirizzati agli assistenti domiciliari riconducibili a barriere culturali e linguistiche, esiguità di risorse e aspetti relazionali. I video sono stati organizzati in sequenze, sottotitolati in spagnolo e romeno e composti da immagini statiche, filmati, commenti audio e testi scritti. La sperimentazione ha evidenziato un riscontro positivo sia dei materiali realizzati sia dell’impatto nei percorsi di apprendimento

Cannabinoid receptor 2 signaling in neurodegenerative disorders: From pathogenesis to a promising therapeutic target

As a consequence of an increasingly aging population, the number of people affected by neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, is rapidly increasing. Although the etiology of these diseases has not been completely defined, common molecular mechanisms including neuroinflammation, excitotoxicity and mitochondrial dysfunction have been confirmed and can be targeted therapeutically. Moreover, recent studies have shown that endogenous cannabinoid signaling plays a number of modulatory roles throughout the central nervous system (CNS), including the neuroinflammation and neurogenesis. In particular, the up-regulation of type-2 cannabinoid (CB2) receptors has been found in a number of neurodegenerative disorders. Thus, the modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neuronal degeneration. For these reasons this review will focus on the CB2 receptor as a promising pharmacological target in a number of neurodegenerative diseases

Altered Expression of the CB1 Cannabinoid Receptor in the Triple Transgenic Mouse Model of Alzheimer's Disease

The endocannabinoid system has gained much attention as a new potential pharmacotherapeutic target in various neurodegenerative diseases, including Alzheimer's disease (AD). However, the association between CB1 alterations and the development of AD neuropathology is unclear and often contradictory. In this study, brain CB1 mRNA and CB1 protein levels were analyzed in 3 × Tg-AD mice and compared to wild-type littermates at 2, 6 and 12 months of age, using in-situ hybridization and immunohistochemistry, respectively. Semiquantitative analysis of CB1 expression focused on the prefrontal cortex (PFC), prelimbic cortex, dorsal hippocampus (DH), basolateral amygdala complex (BLA), and ventral hippocampus (VH), all areas with high CB1 densities that are strongly affected by neuropathology in 3 × Tg-AD mice. At 2 months of age, there was no change in CB1 mRNA and protein levels in 3 × Tg-AD mice compared to Non-Tg mice in all brain areas analyzed. However, at 6 and 12 months of age, CB1 mRNA levels were significantly higher in PFC, DH, and BLA, and lower in VH in 3 × Tg-AD mice compared to wild-type littermates. CB1 immunohistochemistry revealed that CB1 protein expression was unchanged in 3 × Tg-AD at 2 and 6 months of age, while a significant decrease in CB1 receptor immunoreactivity was detected in the BLA and DH of 12-month-old 3 × Tg-AD mice, with no sign of alteration in other brain areas. The altered CB1 levels appear, rather, to be age-and/or pathology-dependent, indicating an involvement of the endocannabinoid system in AD pathology and supporting the ECS as a potential novel therapeutic target for treatment of AD

Alterations of clock gene RNA expression in brain Regions of a triple transgenic model of Alzheimer's Disease

A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer's disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis

Depressive-like behavior is paired to monoaminergic alteration in a murine model of Alzheimer's disease

BACKGROUND: Neuropsychiatric signs are critical in primary caregiving of Alzheimer patients and have not yet been fully investigated in murine models. METHODS: 18-month-old 3×Tg-AD male mice and their wild-type male littermates (non-Tg) were used. The open field test and the elevated plus maze test were used to evaluate anxiety-like behaviors, whereas the Porsolt forced swim test, the tail suspension test, and the sucrose preference test for antidepressant/depression-coping behaviors. Neurochemical study was conducted by microdialysis in freely-moving mice, analyzing the basal and K(+)-stimulated monoamine output in the frontal cortex and ventral hippocampus. Moreover by immunohistochemistry, we analysed the expression of Tyrosin hydroxylase and Tryptophan hydroxylase, which play a key role in the synthesis of monoamines. RESULTS: Aged 3×Tg-AD mice exhibited a higher duration of immobility in the forced swim and tail suspension tests (predictors of depression-like behavior) which was not attenuated by a noradrenaline reuptake inhibitor, desipramine. In the sucrose preference test, 3×Tg-AD mice showed a significantly lower sucrose preference compared to the non-Tg group, without any difference in total fluid intake. In contrast, the motor functions and anxiety-related emotional responses of 3×Tg-AD mice were normal, as detected by the open-field and elevated plus-maze tests. To strengthen these results, we then evaluated the monoaminergic neurotransmissions by in vivo microdialysis and immunohistochemistry. In particular, with the exception of the basal hippocampal dopamine levels, 3×Tg-AD mice exhibited a lower basal extracellular output of amines in the frontal cortex and ventral hippocampus and also a decreased extracellular response to K(+) stimulation. Such alterations occur with obvious local amyloid-β and tau pathologies and without gross alterations in the expression of Tyrosin and Tryptophan hydroxylase. CONCLUSIONS: These results suggest that 3×Tg-AD mice exhibit changes in depression-related behavior involving aminergic neurotrasmitters and provide an animal model for investigating AD with depression

PDIA3 expression is altered in the limbic brain regions of triple-transgenic mouse model of Alzheimer's disease

In the present study, we used a mouse model of Alzheimer's disease (AD) (3×Tg-AD mice) to longitudinally analyse the expression level of PDIA3, a protein disulfide isomerase and endoplasmic reticulum (ER) chaperone, in selected brain limbic areas strongly affected by AD-pathology (amygdala, entorhinal cortex, dorsal and ventral hippocampus). Our results suggest that, while in Non-Tg mice PDIA3 levels gradually reduce with aging in all brain regions analyzed, 3×Tg-AD mice showed an age-dependent increase in PDIA3 levels in the amygdala, entorhinal cortex, and ventral hippocampus. A significant reduction of PDIA3 was observed in 3×Tg-AD mice already at 6 months of age, as compared to age-matched Non-Tg mice. A comparative immunohistochemistry analysis performed on 3×Tg-AD mice at 6 (mild AD-like pathology) and 18 (severe AD-like pathology) months of age showed a direct correlation between the cellular level of Aβ and PDIA3 proteins in all the brain regions analysed, even if with different magnitudes. Additionally, an immunohistochemistry analysis showed the presence of PDIA3 in all post-mitotic neurons and astrocytes. Overall, altered PDIA3 levels appear to be age- and/or pathology-dependent, corroborating the ER chaperone's involvement in AD pathology, and supporting the PDIA3 protein as a potential novel therapeutic target for the treatment of AD

Evaluation of the emotional phenotype and serotonergic neurotransmission of fatty acid amide hydrolase-deficient mice

By enhancing brain anandamide tone, inhibitors of fatty acid amide hydrolase (FAAH) induce anxiolytic-like effects in rodents and enhance brain serotonergic transmission. Mice lacking the faah gene (FAAH(-/-)) show higher anandamide levels. However, their emotional phenotype is still debated and their brain serotonergic tone remained unexplored. In this study, we tested FAAH(-/-) mice in the social interaction and the open field tests performed under different lighting conditions (dim and bright) since variations of the experimental context were proposed to explain opposite findings. Moreover, by microdialysis performed under dim light, we analyzed their serotonergic transmission in frontal cortex (FC) and ventral hippocampus (vHIPP). In both light conditions, FAAH(-/-) mice showed reduced emotionality, compared to wt controls, as suggested by the increased rearing and reduced thigmotaxis displayed in the open field and by the longer time spent in social interaction. Basal serotonergic tone was higher in the FC of mutant mice as compared to control mice, while no difference was observed in the vHIPP. K(+)-induced depolarization produced similar increases of serotonin in both areas of both genotypes. An acute treatment with the CB1 antagonist rimonabant completely abolished the emotional phenotype of FAAH(-/-) mice and prevented the K(+)-stimulated release of serotonin in their FC and vHIPP, without producing any effect in wt mice. Our results support the role of FAAH in the regulation of emotional reactivity and suggest that anandamide-mediated hyperactivation of CB1 is responsible for the emotional phenotype of FAAH(-/-) mice and for their enhanced serotonergic tone