Repeated cocaine exposure during adolescence impairs recognition memory in early adulthood: A role for BDNF signaling in the perirhinal cortex

The perirhinal cortex (PrhC) is critical for object recognition memory; however, information regarding the molecular mechanisms underlying this type of memory following repeated exposure to drugs of abuse during adolescence is unknown. To this end, adolescent or adult rats were exposed to cocaine from postnatal day (PND) 28 to PND 42 or PND 63 to PND 77, respectively. Two weeks later, rats were subjected to the cognitive test named Novel Object Recognition (NOR) test. We found that adolescent, but not adult, cocaine exposure caused a significant impairment in the NOR test, independently from changes in the stress response system. In adolescent saline-treated rats, NOR test up-regulated BDNF and its downstream signaling whereas a downregulation of the same pathway was observed in cocaine-treated rats together with a reduction of Arc/Arg3.1 and PSD95 expression, indicating reduced pro-cognitive structural adaptations in the PrhC. Of note, cocaine-treated adult rats correctly performed in the NOR test indicating intact recognition memory mechanisms, despite a significant cocaine-induced reduction of BDNF levels in the PrhC, suggesting that recognition memory is heavily dependent on BDNF during adolescence whereas during adulthood other mechanisms come into pla

Chronic Restraint Stress Inhibits the Response to a Second Hit in Adult Male Rats : A Role for BDNF Signaling

Depression is a recurrent disorder, with about 50% of patients experiencing relapse. Exposure to stressful events may have an adverse impact on the long-term course of the disorder and may alter the response to a subsequent stressor. Indeed, not all the systems impaired by stress may normalize during symptoms remission, facilitating the relapse to the pathology. Hence, we investigated the long-lasting effects of chronic restraint stress (CRS) and its influence on the modifications induced by the exposure to a second hit on brain-derived neurotrophic factor (BDNF) signaling in the prefrontal cortex (PFC). We exposed adult male Sprague Dawley rats to 4 weeks of CRS, we left them undisturbed for the subsequent 3 weeks, and then we exposed animals to one hour of acute restraint stress (ARS). We found that CRS influenced the release of corticosterone induced by ARS and inhibited the ability of ARS to activate mature BDNF, its receptor Tropomyosin receptor kinase B (TRKB), and their associated intracellular cascades: the TRKB-PI3K-AKT), the MEK-MAPK/ERK, and the Phospholipase C \u3b3 (PLC\u3b3) pathways, positively modulated by ARS in non-stressed animals. These results suggest that CRS induces protracted and detrimental consequences that interfere with the ability of PFC to cope with a challenging situation

PHARMACOLOGICAL APPROACHES TO SARS-CoV-2 INFECTION: FROM DRUG REPOSITIONING FOR COVID-19 TREATMENT TO DISEASE ARREST/PREVENTION WITH MoAbs AND NOVEL ANTIVIRALS

COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is one of the major emergencies that have affected health care systems and society in recent decades. At the end of winter 2021-2022, the number of patients infected with SARS-CoV-2 and especially those suffering from severe COVID-19 is decreasing in Europe. This is due to the protective effect of anti-SARS-CoV-2 vaccines and the increasing number of people who had COVID-19, thus developing a certain immunity. However, vaccines to prevent the disease did not appear until more than one year after the emergence of SARS-CoV-2, so the initial medical approaches to control the disease focused on the existing drugs that were considered suitable for controlling the pathological events caused by the virus as far as was known at the time. Unfortunately, due in part to the limited initial knowledge of the molecular details of the pathology of COVID-19, many of the proposed drugs fell short of expectations and were abandoned. Over time, the challenge of understanding the mechanisms behind COVID-19 has generated a large body of knowledge about how this beta-coronavirus gains control of the host during infection, a knowledge that has been used to redefine treatment strategies by repurposing existing drugs and to explore new drugs. Here, we draw a picture of the major strategies and groups of drugs studied and provide a critical overview of their efficacy and safety based on the available literature data. The main topics covered are repurposed drugs, anticoagulants, anti-cytokine agents, monoclonal antibodies against SARS-CoV-2, and small antiviral molecules

Centella asiatica l. Phytosome improves cognitive performance by promoting bdnf expression in rat prefrontal cortex

A wide range of people in the world use natural remedies as primary approaches against illnesses. Accordingly, understanding the mechanisms of action of phytochemicals has become of great interest. In this context, Centella asiatica L. is extensively used, not only as anti-inflammatory or antioxidant agent but also as brain tonic. On this basis, the purpose of this study was to evaluate whether the chronic administration of C. asiatica L. to adult male rats was able to improve the expression of Bdnf, one of the main mediators of brain plasticity. Moreover, we assessed whether the treatment could affect the cognitive performance in the novel object recognition (NOR) test. We confirmed the presence of the main compounds in the plasma. Furthermore, C. asiatica L. administration induced an increase of Bdnf in the prefrontal cortex, and the administration of the higher dose of the extract was able to improve cognitive performance. Finally, the increase in the preference index in the NOR test was paralleled by a further increase in Bdnf expression. Overall, we highlight the ability of C. asiatica L. to affect brain functions by increasing Bdnf expression and by enhancing the cognitive performance

Short-term withdrawal from developmental exposure to cocaine activates the glucocorticoid receptor and alters spine dynamics

Although glucocorticoid receptors (GRs) contribute to the action of cocaine, their role following developmental exposure to the psychostimulant is still unknown. To address this issue, we exposed adolescent male rats to cocaine (20. mg/kg/day) from post-natal day (PND) 28 to PND 42 and sacrificed them at PND 45 or 90. We studied the medial prefrontal cortex (mPFC), a brain region that is still developing during adolescence. In PND 45 rats we found enhanced GR transcription and translation as well as increased trafficking toward the nucleus of the receptor, with no alteration in plasma corticosterone levels. We also showed reduced expression of the GR co-chaperone FKBP51, that normally keeps the receptor in the cytoplasm, and increased expression of Src1, which cooperates in the activation of GR transcriptional activity, revealing that short withdrawal alters the finely tuned mechanisms regulating GR action. Since activation of GRs regulate dendritic spine morphology, we next investigated spine dynamics in cocaine-withdrawn rats. We found that PSD95, cofilin and F-actin, molecules regulating spine actin network, are reduced in the mPFC of PND 45 rats suggesting reduced spine density, confirmed by confocal imaging. Further, formation of filopodia, i.e. the inactive spines, is enhanced suggesting the formation of non-functional spines. Of note, no changes were found in molecules related to GR machinery or spine dynamics following long-term abstinence, i.e. in adult rats (PND 90). These findings demonstrate that short withdrawal promotes plastic changes in the developing brain via the dysregulation of the GR system and alterations in the spine network

Genome-wide analysis of LPS-induced inflammatory response in the rat ventral hippocampus: Modulatory activity of the antidepressant agomelatine

Objectives: Several studies reported that antidepressant drugs have immune-regulatory effects by acting on specific inflammatory mediators. However, considering the highly complex nature of the inflammatory response, we have adopted an unbiased genome-wide strategy to investigate the immune-regulatory activity of the antidepressant agomelatine in modulating the response to an acute inflammatory challenge. Methods: Microarray analysis was used to identify genes modulated in the ventral hippocampus of adult rats chronically treated with agomelatine (40\u2009mg/kg, os) before being challenged with a single injection of lipopolysaccharide (LPS; 250\u2009\u3bcg/kg, i.p.). Results: The administration of LPS induced the transcription of 284 genes mainly associated with pathways related to the immune/inflammatory system. Agomelatine modulated pathways not only connected to its antidepressant activity, but was also able to prevent the activation of genes induced by LPS. Further comparisons between gene lists of the diverse experimental groups led to the identification of a few transcripts modulated by LPS on which agomelatine has the larger effect of normalisation. Among them, we found the pro-inflammatory cytokine Il-1\u3b2 and, interestingly, the metabotropic glutamatergic transporter Grm2. Conclusions: These results are useful to better characterise the association between depression and inflammation, revealing new potential targets for pharmacological intervention for depression associated to inflammation

The activation of the immune/inflammatory system is associated with the stress-induced anhedonia in rats: effect of pharmacological intervention

Despite the increased knowledge of depression neurobiology, an effective improvement in the overall impact of pharmacotherapy is still lacking, possibly because a number of systems that are affected in mood disorders may not be adequately modulated by pharmacological treatments. Indeed, it is known that this complex disorder is characterized by the interaction of many factors of different nature -i.e. genetic, biological, social and environmental- that act in concert to lead to the development of the illness. Currently, there is strong evidence that depression involves alterations of the immune/inflammatory systems, thus pointing to the importance to characterize this association as well as evaluate the potential impact of pharmacological intervention to interfere with such alterations. On these bases, the purpose of our study was to analyze the cerebral expression of several mediators of the immune/inflammatory system in an animal model of depression based on the environmental component of the disease. Specifically, we used the well-established chronic mild stress (CMS) paradigm to develop a validated rat model of depression in order to elucidate the role of inflammation on the generation of the pathological anhedonic phenotype. Moreover, to evaluate the ability of the pharmacological treatment in modulating the behavioral-associated inflammatory alterations, rats exposed to CMS were also chronically treated with the antidepressants imipramine and with the antipsychotic lurasidone. Our findings indicate that the stress-induced anhedonic phenotype is associated to altered expression of specific mediators of immune/inflammatory system and that pharmacological treatment is not only able to normalize the anhedonic phenotype but also the inflammatory changes. These data suggest that immune/inflammatory alteration may contribute to the subject\u2019s vulnerability of depression and support the idea that immune/inflammatory may serve as viable therapeutic target for more effective antidepressant drugs

Genome-wide analysis of LPS-induced inflammatory response in the rat ventral hippocampus: modulatory activity of chronic treatment with the antidepressant agomelatine

Growing evidence suggests that the activation of the immune/inflammatory system may be associated with depression pathogenesis and, in line with this observation, several studies mainly focused on pro-inflammatory cytokines reported that antidepressant drugs have immunoregulatory effects. However, given the complexity of the inflammatory response, which implies the integration of different mechanisms triggered by various systems, the aim of the present work was to assess the anti-inflammatory properties of the antidepressant agomelatine with an unbiased genome-wide approach by using the microarray technique. Specifically, we analyzed the gene expression profile of the ventral hippocampus, a cerebral area relevant for depression, of adult rats chronically treated with the antidepressant before to receive a systemic injection of lipopolysaccharide (LPS) in comparison with animals treated with saline. To this aim, adult male Sprague-Dawley rats received agomelatine or vehicle for 21 days before being challenged with an acute injection of LPS or saline 16 h after the last drug administration. Animals were sacrificed 2 h after the immune challenge and the ventral hippocampus was dissected and processed for RNA extraction. Transcriptomic analysis was performed using Affymetrix\uae Array and the results were analyzed with Partek Genomics Suite and with Ingenuity Pathway Analyses software. We found that LPS administration induced the transcription of 284 genes mainly associated with pathways related to inflammation. Conversely, chronic treatment with agomelatine alone modulated 105 transcripts belonging to different pathways in saline-treated rats, like the phospolipase C and the CXCR4 pathways. Moreover, the drug was able to prevent the LPS-induced modulation of 91 genes with respect to the control group and of 52 genes with respect to animals treated only with LPS. An intersection analysis between these two lists of genes led to the identification of some transcripts induced by LPS on which agomelatine has the larger effect of normalization. In summary, by using a genome-wide approach, we have highlighted the transcriptional profile of a chronic treatment with agomelatine both at basal state -identifying genes and pathways related to the basal effects of the antidepressant- and in condition of acute inflammation - identifying genes and pathways associated to its anti-inflammatory properties. These genes/pathways might represent potential new targets for pharmacological intervention of depression associated to inflammation

Modulatory activity of chronic treatment with the antidepressant agomelatine on LPS-induced inflammatory response in the rat ventral hippocampus: a genome wide analysis

Given the large body of clinical and preclinical evidence suggesting that the activation of the inflammatory/immune system may contribute to depression pathogenesis, several studies reported that antidepressant drugs have immunoregulatory effects. Accordingly, the aim of the present work was to assess the anti-inflammatory properties of chronic agomelatine treatment with an unbiased genome-wide approach by using the well-established microarray technique. Adult male Sprague-Dawley rats received agomelatine or vehicle for 21 days before being challenged with an acute injection of LPS or saline 16h after the last drug administration. Animals were sacrificed 2h after the immune challenge and the ventral hippocampus was dissected and processed for microarray analysis. The administration of LPS induced the transcription of genes mainly associated with the inflammatory response. Conversely, chronic treatment with agomelatine modulated 105 transcripts belonging to different signaling pathways such as the one of the phospholipase C and the pathway of the chemokine receptor CXCR4, which may contribute to potential neuroprotective effects of the antidepressant. From the transcripts found significantly modulated in the animals treated with agomelatine and challenged with LPS, the antidepressant was able to prevent the LPS-induced modulation of 91 genes with respect to the control group and of 52 genes with respect to animals treated only with LPS. An intersection analysis showed that some transcripts induced by LPS on which the pre-treatment with agomelatine has a large effect of normalization. In summary, we have highlighted the transcriptional profile of a chronic treatment with agomelatine in the rat ventral hippocampus both in basal condition and in condition of acute inflammation, identifying genes and pathways associated to its anti-inflammatory properties that might represent potential new targets for pharmacological intervention of depression associated to inflammation

Long-term abstinence from developmental cocaine exposure alters Arc/Arg3.1 modulation in the rat medial prefrontal cortex

Cocaine is a psychostimulant whose abuse causes a social and economic burden for our society. Most of the published literature deals with acute effects of cocaine or short-term abstinence in adult animals but much less information exists on neuroplastic changes following long-term abstinence. We have recently shown that the long-term abstinence following developmental exposure to cocaine results in increased Activity-Regulated Cytoskeletal- associated protein (Arc/Arg3.1) expression in the crude synaptosomal fraction (Giannotti et al. Int J Neuropsychopharmacology 7(4):625-634, 2014). Given that Arc/Arg3.1 localizes not only at active synapse but also in the nucleus (Okuno et al. Cell 149:886-898, 2012; Korb et al. Nat Neurosci 16:874-883 2013; Bloomer et al. Brain Res 1153:20-33 2007), we investigated Arc/Arg3.1 protein levels in the whole homogenate and the nuclear fraction of animals exposed to cocaine during adolescence. We observed the increased expression of Arc/Arg3.1 in both the fractions, suggesting that up-regulation of Arc/Arg3.1 protein may be partly due to the increased nuclear expression of Arc/Arg3.1 in the medial prefrontal cortex (mPFC) of rats sacrificed at postnatal day 90, following 48 days of abstinence. This effect seems to cause reduced Gria1 transcription. We also found reduced expression of fragile X mental retardation gene (FMR1) which normally inhibits Arc/Arg3.1 translation together with reduced expression of Ubiquitin-protein ligase E3A (Ube3a) that normally causes Arc/Arg3.1 protein degradation via ubiquitination. Further, we found increased expression of metabotropic glutamate receptor 5 (GRM5) which is also involved in the regulation of Arc/Arg3.1 expression. Taken together, our findings show that abstinence from developmental exposure to cocaine is associated with alterations in the finely tuned mechanisms that regulate Arc/Arg3.1 expression