Cellular mechanisms and second messengers: relevance to the psychopharmacology of bipolar disorders

The discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with bipolar disorder and after five decades, lithium continues to be the mainstay of treatment for bipolar disorder. Recent research on the molecular mechanism underlying the therapeutic effect of lithium has focused on how it changes the activities of cellular signal transduction systems, especially the cyclic AMP and phosphomositide second-messenger systems. Considerable data suggest that carbamazepine and valproate (VPA) are an alternative or adjunctive treatment to lithium. VPA, despite being dissimilar structurally to lithium, shares most of the effects of lithium at the level of protein kinase C (PKC). Like lithium, VPA reduces the activity of PKC and reduces the protein levels of different PKC isoforms, however the effects of VPA appear to be largely independent of inositol. The ton-term efficacy of VPA and lithium in bipolar disorder suggested that modulation of gene expression might be an important target for these drugs. Both VPA and lithium altered the expression of the early inducible genes for c-fos and cjun thus promoting the expression of specific proteins. The genes known to be regulated by the AP-1 family of transcription factors include genes for various neuropeptides, neurotrophins, receptors, transcription factors, enzymes, proteins that bind to cytoskeletal elements, and cytoprotective proteins such as bcl-2. In conclusion chronic treatment with lithium and other mood stabilizers, by regulating transcriptional factors, may modulate the expression of a variety of genes that compensate for aberrant signalling associated with the pathophysiology of bipolar disorder

Molecular changes associated with escitalopram response in a stress-based model of depression

Converging evidence points at hypothalamus-pituitary-adrenal (HPA) axis hyperactivity and neuroinflammation as important factors involved in the etiopathogenesis of major depressive disorder (MDD) and in therapeutic efficacy of antidepressants. In this study, we examined the molecular effects associated with a response to a week-long treatment with escitalopram in the chronic escape deficit (CED) model, a validated model of depression based on the induction of an escape deficit after exposure of rats to an unavoidable stress. We confirmed our previous result that a treatment with escitalopram (10 mg/kg) was effective after 7 days in reverting the stress-induced escape deficit in approximately 50% of the animals, separating responders from non-responders. Expression of markers of HPA axis functionality as well as several inflammatory mediators were evaluated in the hypothalamus, a key structure integrating signals from the neuro, immune, endocrine systems. In the hypothalamus of responder animals we observed a decrease in the expression of CRH and its receptors and an increase in GR protein in total and nuclear extracts; this effect was accompanied by a significant decrease in circulating corticosterone in the same cohort. Hypothalamic IL-1\uce\ub2 and TNF\uce\ub1 expression were increased in stressed animals, while CXCL2, IL-6, and ADAM17 mRNA levels were decreased in escitalopram treated rats regardless of the treatment response. These data suggest that efficacy of a one week treatment with escitalopram may be partially mediated by a decrease HPA axis activity, while in the hypothalamus the drug-induced effects on the expression of immune modulators did not correlate with the behavioural outcome

Hypothalamic expression of inflammatory mediators in an animal model of binge eating

Binge eating episodes are characterized by uncontrollable, distressing eating of a large amount of highly palatable food and represent a central feature of bingeing related eating disorders. Research suggests that inflammation plays a role in the onset and maintenance of eating-related maladaptive behavior. Markers of inflammation can be selectively altered in discrete brain region where they can directly or indirectly regulate food intake. In the present study we measured expression levels of different components of cytokine systems (IL-1, IL-6, IL-18, TNF-\uf061 and IFN-&3) and related molecules (iNOS and COX2) in the preoptic and anterior-tuberal parts of the hypothalamus of a validated animal model of binge eating. In this animal model, based on the exposure to both food restriction and frustration stress, binge-like eating behavior for highly palatable food is not shown when animals are exposed to the frustration stress during the estrus phase. We found a characteristic down-regulation of the IL-18/ IL-18 receptor system (with increased expression of the inhibitor of the pro-inflammatory cytokine IL18, IL-18BP, together with a decreased expression of the binding chain of the IL-18 receptor) and a three-fold increase in the expression of iNOS specifically in the anterior- tuberal region of the hypothalamus of animals that develop a binge-like eating behavior. Differently, when food restricted animals were stressed during the estrus phase IL-18 expression increased while iNOS expression was not significantly affected. Considering the role of this region of the hypothalamus in controlling feeding related behavior, this can be relevant in eating disorders and obesity. Our data suggest that by targeting centrally selected inflammatory markers, we may prevent that disordered eating turns into a full blown eating disorder

Disease-induced neuroinflammation and depression

Progression of major depression, a multifactorial disorder with a neuroinflammatory signature, seems to be associated with the disruption of body allostasis. High rates of comorbidity between depression and specific medical disorders, such as, stroke, chronic pain conditions, diabetes mellitus, and human immunodeficiency virus (HIV) infection, have been extensively reported. In this review, we discuss how these medical disorders may predispose an individual to develop depression by examining the impact of these disorders on some hallmarks of neuroinflammation known to be impaired in depressed patients: altered permeability of the blood brain barrier, immune cells infiltration, activated microglia, increased cytokines production, and the role of inflammasomes. In all four pathologies, blood brain barrier integrity was altered, allowing the infiltration of peripheral factors, known to activate resident microglia. Evidence indicated morphological changes in the glial population, increased levels of circulating pro-inflammatory cytokines or increased production of these mediators within the brain, all fundamental in neuroinflammation, for the four medical disorders considered. Moreover, activity of the kynurenine pathway appeared to be enhanced. With respect to the inflammasome NLRP3, a new target whose role in neuroinflammation is emerging as being important, accumulating data suggest its involvement in the pathogenesis of brain injury following stroke, chronic pain conditions, diabetes mellitus or in HIV associated immune impairment. Finally, data gathered over the last 10 years, indicate and confirm that depression, stroke, chronic pain, diabetes, and HIV infection share a combination of underlying molecular, cellular and network mechanisms leading to a general increase in the neuroinflammatory burden for the individual

Identification and characterization of the kynurenine pathway in the pond snail Lymnaea stagnalis

Dysregulation of the kynurenine pathway (KP) is implicated in many human diseases and disorders, from immunological, metabolic, neurodegenerative, and neuropsychiatric conditions to cancer, and represents an appealing target for new therapeutic approaches. In this intricate scenario, invertebrates, like Lymnaea stagnalis (LS), provide a flexible tool to unravel the complexity of the KP. Starting from the available LS genome and transcriptome, we identified putative transcripts of all KP enzymes containing an ORF; each predicted protein possessed a high degree of sequence conservation to known orthologues of other invertebrate and vertebrate model organisms. Sequences were confirmed by qualitative PCR and sequencing. At the same time, the qRT-PCR analysis revealed that Lym IDO-like, Lym TDO-like, Lym AFMID-like, Lym KMO-like, Lym AADAT-like, Lym KYAT I/III-like, Lym KYNU-like, Lym HAAO-like, and Lym ACMSD-like showed widespread tissue expression. Then, tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxy-kynurenine, xanthurenic acid, picolinic acid, and quinolinic acid were identified in the hemolymph of LS by UHPLC-Q exactive mass spectrometer. Our study provides the most thorough characterization to date of the KP in an invertebrate model, supporting the value of LS for future functional studies of this pathway at the cellular, synaptic, and behavioral levels

Cognitive deficits and changes in gene expression of NMDA receptors after prenatal methylmercury exposure.

Previous studies showed learning and memory deficit in adult rats that were prenatally exposed to methylmercury chloride (MMC) in an advanced stage of pregnancy (15 days). Under these conditions, the cognitive deficits found at 60 days of age paralleled particularly changes in the N-methyl-D-aspartate (NMDA) receptor characteristics. In the present study, we report the behavioral effects of a single oral dose of MMC (8 mg/kg) administered earlier at gestational day 8. The use of different learning and memory tests (passive avoidance, object recognition, water maze) showed a general cognitive impairment in the in utero-exposed rats tested at 60 days of age compared with matched controls. Considering the importance of the glutamatergic receptor system and its endogenous ligands in learning and memory process regulation, we surmised that MMC could affect the gene expression of NMDA receptor subtypes. The use of a sensitive RNase protection assay allowed the evaluation of gene expression of two families of NMDA receptors (NR-1 and NR-2 subtypes). The result obtained in 60-day-old rats prenatally exposed to MMC, showed increased mRNA levels of the NR-2B subunit in the hippocampus but not in the frontal cortex. The data suggest that the behavioral abnormalities of MMC-exposed rats might be ascribed to a neurotoxic effect of the metal that alters the gene expression of a specific NMDA receptor subunit in the hippocampus

Carnosine Protects Macrophages against the Toxicity of Aβ1-42 Oligomers by Decreasing Oxidative Stress

Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide has well-known antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of neurodegenerative disorders such as Alzheimer’s disease (AD). In this disease, peripheral infiltrating macrophages play a substantial role in the clearance of amyloid beta (Aβ) peptides from the brain. Correspondingly, in patients suffering from AD, defects in the capacity of peripheral macrophages to engulf Aβ have been reported. The effects of carnosine on macrophages and oxidative stress associated with AD are consequently of substantial interest for drug discovery in this field. In the present work, a model of stress induced by Aβ1-42 oligomers was investigated using a combination of methods including trypan blue exclusion, microchip electrophoresis with laser-induced fluorescence, flow cytometry, fluorescence microscopy, and high-throughput quantitative real-time PCR. These assays were used to assess the ability of carnosine to protect macrophage cells, modulate oxidative stress, and profile the expression of genes related to inflammation and pro- and antioxidant systems. We found that pre-treatment of RAW 264.7 macrophages with carnosine counteracted cell death and apoptosis induced by Aβ1-42 oligomers by decreasing oxidative stress as measured by levels of intracellular nitric oxide (NO)/reactive oxygen species (ROS) and production of peroxynitrite. This protective activity of carnosine was not mediated by modulation of the canonical inflammatory pathway but instead can be explained by the well-known antioxidant and free-radical scavenging activities of carnosine, enhanced macrophage phagocytic activity, and the rescue of fractalkine receptor CX3CR1. These new findings obtained with macrophages challenged with Aβ1-42 oligomers, along with the well-known multimodal mechanism of action of carnosine in vitro and in vivo, substantiate the therapeutic potential of this dipeptide in the context of AD pathology

Medicine and psychiatry in Western culture: Ancient Greek myths and modern prejudices

The origins of Western culture extensively relate to Ancient Greek culture. While many ancient cultures have contributed to our current knowledge about medicine and the origins of psychiatry, the Ancient Greeks were among the best observers of feelings and moods patients expressed towards medicine and toward what today is referred to as 'psychopathology'. Myths and religious references were used to explain what was otherwise impossible to understand or be easily communicated. Most ancient myths focus on ambiguous feelings patients may have had towards drugs, especially psychotropic ones. Interestingly, such prejudices are common even today