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

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

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