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

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

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

Modulation of BDNF expression by repeated treatment with the novel antipsychotic lurasidone under basal condition and in response to acute stress

It is known that long-term treatment with antipsychotic drugs (APDs) produces neuroadaptive changes through the modulation of different proteins that, by enhancing neuronal plasticity and cellular resiliency, may improve core disease symptoms. The aim of this study was to investigate the ability of chronic treatment with the novel antipsychotic lurasidone to modulate BDNF expression in hippocampus and prefrontal cortex, under basal conditions or in response to an acute stress, a major precipitating element in psychiatric disorders. By means of real-time PCR, we found that (1) chronic lurasidone treatment increases total BDNF mRNA levels in rat prefrontal cortex and, to less extent, in hippocampus; (2) the modulation of BDNF mRNA levels in response to acute swim stress in lurasidone-treated rats was markedly potentiated in hippocampus, and to less extent in prefrontal cortex, through the selective regulation of different neurotrophin isoforms. The increase of BDNF mRNA levels in prefrontal cortex was paralleled by an enhancement of mature BDNF protein levels. In conclusion, repeated exposure to lurasidone regulates BDNF expression, through a finely tuned modulation of its transcripts. This effect may contribute to the amelioration of functions, such as cognition, closely associated with neuronal plasticity, which are deteriorated in schizophrenia patients

Synaptoproteomic analysis of a rat gene-environment model of depression reveals involvement of energy metabolism and cellular remodeling pathways

Major depression is a severe mental illness that causes heavy social and economic burden worldwide. A number of studies have shown that interaction between individual genetic vulnerability and environmental risk factors, such as stress, is crucial in psychiatric pathophysiology. In particular, the experience of stressful events in childhood, such as neglect, abuse or parent loss, was found to increase the risk for development of depression in adult life. Here, to reproduce the gene x environment interaction, we employed an animal model that combines genetic vulnerability with early-life stress

Chronic treatment with agomelatine or venlafaxine reduces depolarization-evoked glutamate release from hippocampal synaptosomes

Background: Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Agomelatine, a new antidepressant endowed with MT1/MT2 agonist and 5-HT2C serotonergic antagonist properties, has shown efficacy at both preclinical and clinical levels. Results: Chronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. No changes were observed in GABA release. This effect was accompanied by reduced accumulation of SNARE protein complexes, the key molecular effector of vesicle docking, priming and fusion at presynaptic membranes. Conclusions: Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus. Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release

Serotonin and Dopamine Protect from Hypothermia/Rewarming Damage through the CBS/ H2S Pathway

Biogenic amines have been demonstrated to protect cells from apoptotic cell death. Herein we show for the first time that serotonin and dopamine increase H2S production by the endogenous enzyme cystathionine-β-synthase (CBS) and protect cells against hypothermia/rewarming induced reactive oxygen species (ROS) formation and apoptosis. Treatment with both compounds doubled CBS expression through mammalian target of rapamycin (mTOR) and increased H2S production in cultured rat smooth muscle cells. In addition, serotonin and dopamine treatment significantly reduced ROS formation. The beneficial effect of both compounds was minimized by inhibition of their re-uptake and by pharmacological inhibition of CBS or its down-regulation by siRNA. Exogenous administration of H2S and activation of CBS by Prydoxal 5′-phosphate also protected cells from hypothermic damage. Finally, serotonin and dopamine pretreatment of rat lung, kidney, liver and heart prior to 24 h of hypothermia at 3°C followed by 30 min of rewarming at 37°C upregulated the expression of CBS, strongly reduced caspase activity and maintained the physiological pH compared to untreated tissues. Thus, dopamine and serotonin protect cells against hypothermia/rewarming induced damage by increasing H2S production mediated through CBS. Our data identify a novel molecular link between biogenic amines and the H2S pathway, which may profoundly affect our understanding of the biological effects of monoamine neurotransmitters