A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds' activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan

The behavioral and neural basis of empathic blame

Mature moral judgments rely both on a perpetrator’s intent to cause harm, and also on the actual harm caused—even when unintended. Much prior research asks how intent information is represented neurally, but little asks how even unintended harms influence judgment. We interrogate the psychological and neural basis of this process, focusing especially on the role of empathy for the victim of a harmful act. Using fMRI, we found that the ‘empathy for pain’ network was involved in encoding harmful outcomes and integrating harmfulness information for different types of moral judgments, and individual differences in the extent to which this network was active during encoding and integration of harmfulness information determined severity of moral judgments. Additionally, activity in the network was down-regulated for acceptability, but not blame, judgments for accidental harm condition, suggesting that these two types of moral evaluations are neurobiologically dissociable. These results support a model of “empathic blame”, whereby the perceived suffering of a victim colors moral judgment of an accidental harmdoer

Neuroanatomical correlates of forgiving unintentional harms

Mature moral judgments rely on the consideration of the perpetrator’s mental state as well as the harmfulness of the outcomes produced. Prior work has focused primarily on the functional correlates of how intent information is neurally represented for moral judgments, but few studies have investigated whether individual differences in neuroanatomy can also explain variation in moral judgments. In the current study, we conducted voxel-based morphometry analyses combined with functional magnetic resonance imaging to address this question. We found that local grey matter volume in left anterior superior temporal sulcus, a region in the functionally defined theory of mind or mentalizing network, was associated with the degree to which participants relied on information about innocent intentions to forgive accidental harms. Our findings provide further support for the key role of mentalizing in the forgiveness of accidental harms and contribute preliminary evidence for the neuroanatomical basis of individual differences in moral judgments

Reasoning supports utilitarian resolutions to moral dilemmas across diverse measures

Sacrificial moral dilemmas elicit a strong conflict between the motive to not personally harm someone and the competing motive to achieving the greater good, which is often described as the \u201cutilitarian\u201d response. Some prior research suggests that reasoning abilities and deliberative cognitive style are associated with endorsement of utilitarian solutions, but, as has more recently been emphasized, both conceptual and methodological issues leave open the possibility that utilitarian responses are due instead to a reduced emotional response to harm. Across 8 studies, using self-report, behavioral performance, and neuroanatomical measures, we show that individual differences in reasoning ability and cognitive style of thinking are positively associated with a preference for utilitarian solutions, but bear no relationship to harm-relevant concerns. These findings support the dual-process model of moral decision making and highlight the utility of process dissociation method

In vitro and in vivo study of butyrylfentanyl and 4‐fluorobutyrylfentanyl in female and male mice: Role of the CRF1 receptor in cardiorespiratory impairment

Background and Purpose: Fentanyl analogues have been implicated in many cases of intoxication and death with overdose worldwide. The aim of this study is to investigate the pharmaco-toxicology of two fentanyl analogues: butyrylfentanyl (BUF) and 4-fluorobutyrylfentanyl (4F-BUF). Experimental Approach: In vitro, we measured agonist opioid receptor efficacy, potency, and selectivity and ability to promote interaction of the mu receptor with G protein and beta-arrestin 2. In vivo, we evaluated thermal antinociception, stimulated motor activity and cardiorespiratory changes in female and male CD-1 mice injected with BUF or 4F-BUF (0.1-6 mgkg(-1)). Opioid receptor specificity was investigated using naloxone (6 mgkg(-1)). We investigated the possible role of stress in increasing cardiorespiratory toxicity using the corticotropin-releasing factor 1 (CRF1) antagonist antalarmin (10 mgkg(-1)). Key Results: Agonists displayed the following rank of potency at mu receptors: fentanyl > 4F-BUF > BUF. Fentanyl and BUF behaved as partial agonists for the beta-arrestin 2 pathway, whereas 4F-BUF did not promote beta-arrestin 2 recruitment. In vivo, we revealed sex differences in motor and cardiorespiratory impairments but not antinociception induced by BUF and 4F-BUF. Antalarmin alone was effective in blocking respiratory impairment induced by BUF in both sexes but not 4F-BUF. The combination of naloxone and antalarmin significantly enhanced naloxone reversal of the cardiorespiratory impairments induced by BUF and 4F-BUF in mice. Conclusion and Implications: In this study, we have uncovered a novel mechanism by which synthetic opioids induce respiratory depression, shedding new light on the role of CRF1 receptors in cardiorespiratory impairments by mu agonists

In vitro and in vivo pharmaco-dynamic study of the novel fentanyl derivatives: Acrylfentanyl, Ocfentanyl and Furanylfentanyl

Fentanyl derivatives (FENS) belongs to the class of Novel Synthetic Opioids that emerged in the illegal drug market of New Psychoactive Substances (NPS). These substances have been implicated in many cases of intoxication and death with overdose worldwide. Therefore, the aim of this study is to investigate the pharmacodynamic profiles of three fentanyl (FENT) analogues: Acrylfentanyl (ACRYLF), Ocfentanyl (OCF) and Furanylfentanyl (FUF). In vitro, we measured FENS opioid receptor efficacy, potency, and selectivity in calcium mobilization studies performed in cells coexpressing opioid receptors and chimeric G proteins and their capability to promote the interaction of the mu receptor with G protein and beta-arrestin 2 in bioluminescence resonance energy transfer (BRET) studies. In vivo, we investigated the acute effects of the systemic administration of ACRYLF, OCF and FUF (0.01-15 mg/kg i.p.) on mechanical and thermal analgesia, motor impairment, grip strength and cardiorespiratory changes in CD-1 male mice. Opioid receptor specificity was investigated in vivo using naloxone (NLX; 6 mg/kg i.p) pre-treatment. In vitro, the three FENS were able to activate the mu opioid receptor in a concentration dependent manner with following rank order potency: FUF > FENT=OCF > ACRYLF. All compounds were able to elicit maximal effects similar to that of dermorphin, with the exception of FUF which displayed lower maximal effects thus behaving as a partial agonist. In the BRET G-protein assay, all compounds behaved as partial agonists for the beta-arrestin 2 pathway in comparison with dermorphin, whereas FUF did not promote beta-arrestin 2 recruitment, behaving as an antagonist. In vivo, all the compounds increased mechanical and thermal analgesia with following rank order potency ACRYLF = FENT > FUF > OCF and impaired motor and cardiorespiratory parameters. Among the substances tested, FUF showed lower potency for cardiorespiratory and motor effects. These findings reveal the risks associated with the use of FENS and the importance of studying the pharmaco-dynamic properties of these drugs to better understand possible therapeutic interventions in the case of toxicity

Nociceptin/orphanin FQ inhibits the survival and axon growth of midbrain dopaminergic neurons through a p38-MAPK dependent mechanism

Nociceptin/orphanin FQ (N/OFQ) is an opioid-like neuropeptide that binds and signals through a G-protein-coupled receptor called the N/OFQ peptide (NOP) receptor. N/OFQ and the NOP receptor are expressed in the midbrain and have been implicated in the pathogenesis of Parkinson’s disease (PD). Genetic removal of the N/OFQ precursor partially protects midbrain dopaminergic neurons from 1-methyl-4-phenylpyridine-induced toxicity, suggesting that endogenous N/OFQ may be detrimental to dopaminergic neurons. However, whether N/OFQ directly affects the survival and growth of dopaminergic neurons is unknown. Here, we show that N/OFQ has a detrimental effect on the survival of dopaminergic neurons and the growth of their axons in primary cultures of the E14 rat ventral mesencephalon. N/OFQ potentiates the effects of the neurotoxins 6-hydroxydopamine and 1-methyl-4-phenylpyridinium through p38-MAPK signalling. We also show that like α-synuclein, there is a significant reduction in N/OFQ messenger RNA (mRNA) expression in the midbrain of patients with Parkinson’s disease. These results demonstrate for the first time that N/OFQ is detrimental to the survival and growth of dopaminergic neurons and that its expression is altered in the midbrain of patients with Parkinson’s disease

A prospective cohort analysis of the prevalence and predictive factors of delayed discharge after laparoscopic cholecystectomy in Italy: the DeDiLaCo Study

Background: The concept of early discharge ≤24 hours after Laparoscopic Cholecystectomy (LC) is still doubted in Italy. This prospective multicentre study aims to analyze the prevalence of patients undergoing elective LC who experienced a delayed discharge >24 hours in an extensive Italian national database and identify potential limiting factors of early discharge after LC. Methods: This is a prospective observational multicentre study performed from January 1, 2021 to December 31, 2021 by 90 Italian surgical units. Results: A total of 4664 patients were included in the study. Clinical reasons were found only for 850 patients (37.7%) discharged >24 hours after LC. After excluding patients with nonclinical reasons for delayed discharge >24 hours, 2 groups based on the length of hospitalization were created: the Early group (≤24 h; 2414 patients, 73.9%) and the Delayed group (>24 h; 850 patients, 26.1%). At the multivariate analysis, ASA III class ( P <0.0001), Charlson's Comorbidity Index (P=0.001), history of choledocholithiasis (P=0.03), presence of peritoneal adhesions (P<0.0001), operative time >60 min (P<0.0001), drain placement (P<0.0001), pain ( P =0.001), postoperative vomiting (P=0.001) and complications (P<0.0001) were independent predictors of delayed discharge >24 hours. Conclusions: The majority of delayed discharges >24 hours after LC in our study were unrelated to the surgery itself. ASA class >II, advanced comorbidity, the presence of peritoneal adhesions, prolonged operative time, and placement of abdominal drainage were intraoperative variables independently associated with failure of early discharge