Acute Pretreatment Research Articles

Evaluating the effects of empagliflozin in preventing myocardial injury in patients undergoing percutaneous coronary intervention: A double-blind, randomized clinical trial.

Percutaneous Coronary Intervention (PCI) is a fundamental procedure for coronary artery disease management, yet the risk of adverse events such periprocedural myocardial injury (PMI) persists. This double-blind, randomized clinical trial aims to assess the efficacy of empagliflozin in preventing myocardial injury during PCI procedure. A total of 90 patients were randomly assigned to two groups A and B; Group A as the intervention group received empagliflozin 25 mg 24 hours before and empagliflozin 10 mg 1-2 hours before coronary intervention and group Bas the control group received placebo at similar intervals. The primary outcome involved comparing baseline, 8-hour, and 24-hour cTnI and baseline and 24-hour hs-CRP levels after PCI in both groups to measure the incidence of periprocedural myocardial injury (PMI) and anti-inflammatory effects of empagliflozin. Baseline cTnI levels with P=0.955, 8 hours after PCI with P=0.469, and 24 hours after the intervention with P=0.980 were not statistically different in the two groups. Baseline levels of hs-CRP in both intervention and control groups were not statistically significantly different (P=0.982). Also, there was no statistically significant difference in hs-CRP levels 24 hours after PCI in two groups (P=0.198). Finally, the results showed that MACEs did not occur in any of the groups. The results of this trial could not express the advantages of acute pretreatment with empagliflozin in preventing PCI-related myocardial injury.

The physicochemical characteristics and antidepressant-like effects of a polysaccharide-rich fraction from Schisandra chinensis (Turcz.) Baill in behavioral despair mice and olfactory bulbectomy-induced depression-like mice

Ethnopharmacological relevanceThe dried fruit of Schisandra chinensis (Turcz.) Baill (S. chinensis) is widely used in treating central nervous system disorders. Increasing evidence has suggested that alcohol-soluble extracts and lignans from S. chinensis could significantly ameliorate depression-like behaviors in animal models, while there was little research on the potential of alcohol-insoluble polysaccharides as a candidate in the treatment of depression. Aim of the studyOur research was designed to explore both the physicochemical characteristics and antidepressant-like effects of an alcohol-insoluble polysaccharide-rich fraction named SCP from S. chinensis. Simultaneously, the underlying mechanisms were elucidated in the study. Materials and methodsThe physicochemical characteristics were accomplished by colorimetric assays, CE, HPGPC, and FT-IR. Behavioral despair testing accompanied by LAT were processed to promptly assess the antidepressant-like effects of SCP in mice. Then OBX-induced mice were established to explore the impacts of chronic co-treatments with SCP. Furthermore, effects of SCP on the HPA axis, oxidant/antioxidant system, neurotrophic and synaptic factors, and gut microbiota in OBX-induced mice were detected through ELISA and 16S rDNA (V3 + V4 regions) gene sequencing. ResultsSCP is a polysaccharide-rich fraction mainly comprised of xylose, glucose, rhamnose, galactose, mannose, and galacturonic acid in ratios of 0.27, 5.09, 0.24, 1.00, 0.63, and 2.86, of which the MW distribution ranges from 681 to 3232 Da. Acute pre-treatment with SCP (200 mg/kg, i.g.) remarkably reduced mice’s immobility in the FST without motor stimulation. Prolonged pre-treatments effectively enhanced the effects of SCP on the behavioral despair testing in mice. Chronic co-treatments with SCP (50, 200, and 800 mg/kg, i.g.) could ameliorate the slow increase of body weight and behavioral abnormality of OBX-induced mice in systemic behavioral testing. SCP (200 mg/kg) also successfully restored hyperactivity of the HPA axis, oxidative damage in the liver, neurotrophic disturbance and abnormal synaptic plasticity in the hippocampus, and dysregulation of gut microbiota in OBX-induced mice. ConclusionSCP exerts noteworthy antidepressant-like impacts on behavioral despair mice and OBX-induced mice via multiple targets, indicating a potential therapeutic candidate in depression therapy.

Rapid cold hardening modifies ion regulation to delay anoxia-induced spreading depolarization in the CNS of the locust

Insects experience different kinds of environmental stresses that can impair neural performance, leading to spreading depolarization (SD) of nerve cells and neural shutdown underlying coma. SD is associated with a sudden loss of ion, notably K+, homeostasis in the central nervous system. The sensitivity of an insect's nervous system to stress (e.g., anoxia) can be modulated by acute pre-treatment. Rapid cold hardening (RCH) is a form of preconditioning, in which a brief exposure to low temperature can enhance the stress tolerance of insects. We used a pharmacological approach to investigate whether RCH affects anoxia-induced SD in the locust, Locusta migratoria, via one or more of the following homeostatic mechanisms: (1) Na+/K+-ATPase (NKA), (2) Na+/K+/2Cl− co-transporter (NKCC), and (3) voltage-gated K+ (Kv) channels. We also assessed abundance and phosphorylation of NKCC using immunoblotting. We found that inhibition of NKA or Kv channels delayed the onset of anoxia-induced SD in both control and RCH preparations. However, NKCC inhibition preferentially abrogated the effect of RCH. Additionally, we observed a higher abundance of NKCC in RCH preps but no statistical difference in its phosphorylation level, indicating the involvement of NKCC expression or degradation as part of the RCH mechanism.

Comparison of preventive and therapeutic effects of continuous exercise on acute lung injury induced with methotrexate.

Methotrexate (Mtx) is used to treat various diseases, including cancer, arthritis and other rheumatic diseases. However, it induces oxidative stress and pulmonary inflammation by stimulating production of reactive oxygen species and cytokines. Considering the positive effects of physical activity, our goal was to investigate the preventive and therapeutic role of continuous training (CT) on Mtx-induced lung injury in rats. The rats were divided into five groups of 14 animals: a control group (C); a continuous exercise training group (CT; healthy rats that experienced CT); an acute lung injury with Mtx group (ALI); a pretreatment group with CT (the rats experienced CT before ALI induction), and a post-treatment group with CT (the rats experienced CT after ALI induction). One dose of 20mg/kg Mtx intraperitoneal was administered in the Mtx and training groups. Forty-eight hours after the last exercise session all rats were sacrificed. According to our results, the levels of tumour necrosis factor-α (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO), GATA binding protein 3 (GATA3) and caspase-3 in the ALI group significantly increased compared to the control group, and the levels of superoxide dismutase (SOD), glutathione peroxidase (GPX), total antioxidant capacity (TAC), interleukin-10 (IL-10), forkhead box protein 3 (FOXP3), and T-bet decreased. In contrast, compared to the acute lung injury group, pretreatment and treatment with CT reduced TNF-α, MDA, MPO, GATA3 and caspase-3 and increased SOD, GPX, TAC, IL-10, FOXP3 and T-bet levels. The effects of CT pretreatment were more significant than the effects of CT post-treatment. Continuous exercise training effectively reduced oxidative stress and inflammatory cytokines and ameliorated Mtx-induced injury, and the effects of CT pretreatment were more significant than the effects of CT post-treatment. NEW FINDINGS: What is the central question of this study? Considering the high prevalence of lung injury in society, does exercise as a non-pharmacological intervention have ameliorating effects on lung injury? What is the main finding and its importance? Exercise can have healing effects on the lung after pulmonary injury through reducing inflammation, oxidative stress and apoptosis. Considering the lower side effects of exercise compared to drug treatments, the results of this study may be useful in the future.

Effects of environmental and pharmacological manipulations on cocaine-vs-negative reinforcer choice in male and female rats.

The adverse consequences of human addictive drug use could be the result of either addictive drug consumption resulting in punishment (e.g., incarceration) or failure to engage in negative-reinforced behaviors that might compete with drug-maintained behaviors (e.g., contingency management strategies that reset payment amounts for drug free urines). The goal of the present study was to establish a discrete-trial cocaine-vs-negative reinforcer (SNR) choice procedure where rats were presented with a simplified model of this conflict: choose negative reinforcement (i.e., escape or avoid foot shock) or choose an intravenous (IV) cocaine infusion followed by an inescapable shock. Responding was maintained in male and female rats by IV cocaine infusions (0.32-1.8 mg/kg/inf) and a SNR (0.1-0.7 mA shock) under a discrete-trial concurrent"choice" schedule during daily sessions. Following parametric reinforcer magnitude and response requirement experiments, the effects of 12 h extended access cocaine self-administration and acute diazepam (0.32-10 mg/kg, IP) pretreatment were determined on cocaine-vs-SNR choice. Negative reinforcement was chosen over all cocaine doses. Lowering shock magnitude or increasing SNR response requirement failed to promote behavioral reallocation towards cocaine. Extended access cocaine self-administration sessions resulted in high daily cocaine intakes but failed to significantly increase cocaine choice in all (19) but one rat. Acute diazepam pretreatment also did not alter choice behavior up to doses that produced behavioral depression. These results suggest that SNRs may be a source of reinforcement that effectively compete with and mitigate maladaptive addictive drug-maintained behaviors in the general population.

A Postsynaptic Density Immediate Early Gene-Based Connectome Analysis of Acute NMDAR Blockade and Reversal Effect of Antipsychotic Administration.

Although antipsychotics' mechanisms of action have been thoroughly investigated, they have not been fully elucidated at the network level. We tested the hypothesis that acute pre-treatment with ketamine (KET) and administration of asenapine (ASE) would modulate the functional connectivity of brain areas relevant to the pathophysiology of schizophrenia, based on transcript levels of Homer1a, an immediate early gene encoding a key molecule of the dendritic spine. Sprague-Dawley rats (n = 20) were assigned to KET (30 mg/kg) or vehicle (VEH). Each pre-treatment group (n = 10) was randomly split into two arms, receiving ASE (0.3 mg/kg), or VEH. Homer1a mRNA levels were evaluated by in situ hybridization in 33 regions of interest (ROIs). We computed all possible pairwise Pearson correlations and generated a network for each treatment group. Acute KET challenge was associated with negative correlations between the medial portion of cingulate cortex/indusium griseum and other ROIs, not detectable in other treatment groups. KET/ASE group showed significantly higher inter-correlations between medial cingulate cortex/indusium griseum and lateral putamen, the upper lip of the primary somatosensory cortex, septal area nuclei, and claustrum, in comparison to the KET/VEH network. ASE exposure was associated with changes in subcortical-cortical connectivity and an increase in centrality measures of the cingulate cortex and lateral septal nuclei. In conclusion, ASE was found to finely regulate brain connectivity by modelling the synaptic architecture and restoring a functional pattern of interregional co-activation.

Pramipexole inhibits formalin-induce acute and long-lasting mechanical hypersensitivity via NF-kB pathway in rats.

Pain is one of the most frequent causes for patients to seek medical care. It interferes with daily functioning and affects the quality of life of the patient. There is a clear need to investigate nonopioid or non-nonsteroidal anti-inflammatory drug alternatives for the treatment of pain. In this study, we determined the effect of acute pre- and posttreatment with pramipexole (PPX), a dopamine D2/D3 selective agonist, on formalin 1%-induced acute and long-lasting nociceptive behavior sensitivity in rats. Moreover, we sought to investigate whether the antiallodynic and antihyperalgesic effect induced by PPX was mediated through the nuclear factor-κB(NF-kB) signaling pathway. Moreover, acute systemic pretreatment with PPX (1 and 3 mg/kg, ip) suppressed the formalin-induced nociceptive behavior during both phases of the formalin test and the development of formalin-induced secondary mechanical allodynia and hyperalgesia in both paws. Acute systemic posttreatment with PPX (3 mg/kg, ip) reverted the formalin-induced long-lasting secondary mechanical allodynia and hyperalgesia. Furthermore, PPX inhibits the protein expression of NF-κB-p65 and the levels of tumor necrosis factor-α and interleukin-1β in the spinal cord of animals with secondary mechanical allodynia and hyperalgesia induced by formalin. These data suggest that PPX has a potential role in producing anti-inflammatory activity. Moreover, the antiallodynic and antihyperalgesic effects induced by PPX can be mediated through the NF-kB signaling pathway.

Evaluation of the 5-HT2C receptor drugs RO 60-0175, WAY 161503 and mirtazepine in a preclinical model of comorbidity of depression and cocaine addiction

BackgroundEpidemiological data indicate a high rate of comorbidity of depression and cocaine use disorder (CUD). The role of serotonin 2C (5-HT2C) receptors in the mechanisms responsible for the coexistence of depression and CUD was not investigated.MethodsWe combined bilateral olfactory bulbectomy (OBX), an animal model of depression, with intravenous cocaine self-administration and extinction/reinstatement in male rats to investigate two 5-HT2C receptor agonists (Ro 60-0175 (RO) and WAY 161503 (WAY)) and the 5-HT2C-receptor preferring antagonist mirtazapine (MIR; an antidepressant), with the goal of determining whether these drugs alter cocaine-induced reinforcement and seeking behaviors. Additionally, neurochemical analyses were performed following cocaine self-administration and its abstinence period in the brain structures in OBX rats and SHAM-operated controls.ResultsAcute administration of RO reduced, while WAY non-significantly attenuated cocaine reinforcement in both rat phenotypes. Moreover, RO or WAY protected against cocaine-seeking behavior after acute or after repeated drug administration during extinction training in OBX and SHAM rats. By contrast, acutely administered MIR did not alter cocaine reinforcement in both rat phenotypes, while it’s acute (but not repeated) pretreatment reduced cocaine-seeking in OBX and SHAM rats. In neurochemical analyses, cocaine reinforcement increased 5-HT2C receptor levels in the ventral hippocampus; a preexisting depression-like phenotype enhanced this effect. The 10-daily cocaine abstinence reduced 5-HT2C receptor expression in the dorsolateral striatum, while the coexistence of depression and CUD enhanced local receptor expression.ConclusionThe results support a key role of 5-HT2C receptors for treating CUD and comorbid depression and CUD. They may be backs the further research of pharmacological strategies with drug targeting receptors.Graphical abstract

Simvastatin protects against intestinal ischemia/reperfusion-induced pulmonary artery dysfunction

AimsThe lung is an important target organ damage in intestinal ischemia/reperfusion (II/R), but mechanisms involved in II/R-induced pulmonary artery (PA) dysfunction, as well as its treatment, are not clear. The present study aimed to investigate the mechanisms involved in the II/R-induced PA dysfunction and a possible protective role of acute simvastatin pretreatment. Main methodsMale Wistar rats were subjected to occlusion of the superior mesenteric artery for 45 min followed by 2 h reperfusion (II/R) or sham-operated surgery (sham). In some rats, simvastatin (20 mg/kg, oral gavage) was administrated 1 h before II/R. Key findingsII/R reduced acetylcholine-induced relaxation and phenylephrine-induced contraction of PA segments, which were prevented by acute simvastatin pretreatment in vivo or restored by inducible nitric oxide synthase (iNOS) inhibition in situ with 1400 W. Elevated reactive oxygen species (ROS) levels and higher nuclear translocation of nuclear factor kappa B (NFκB) subunit p65 were observed in PA of II/R rats and prevented by simvastatin. Moreover, simvastatin increased superoxide dismutase (SOD) activity and endothelial nitric oxide synthase (eNOS) expression in PA of the II/R group as well as prevented the increased levels of interleukin (IL)-1β and IL-6 in lung explants following II/R. SignificanceThe study suggests that pretreatment with a single dose of simvastatin prevents the II/R-induced increase of inflammatory factors and oxidative stress, as well as PA endothelial dysfunction and adrenergic hyporreactivity. Therefore, acute simvastatin administration could be therapeutic for pulmonary vascular disease in patients suffering from intestinal ischemic events.

Acute SGLT-2i treatment improves cardiac efficiency during myocardial ischemia independent of Na+/H+ exchanger-1

AimsSodium glucose co-transporter 2 inhibitors (SGLT2i) demonstrate cardioprotective benefits independent of a glucose lowering effect including preservation of cardiac function during a myocardial ischemia. Sodium‑hydrogen exchanger-1 (NHE-1), has been hypothesized to contribute to the cardiac effects of SGLT2i. We characterized the beneficial effects of acute pre-ischemia exposure to SGLT2i and explored the possibility that these effects are explained by NHE-1 inhibition. Methods and resultsSwine were anesthetized and instrumented for invasive hemodynamic measurements. After baseline data collection, swine received a 15–30 min intravenous infusion of vehicle (DMSO), the SGLT2i canagliflozin (~1 mg/kg), or the NHE-1 inhibitor cariporide (~0.03 mg/kg) ending immediately prior to occlusion of the left circumflex artery. Measurements were obtained at baseline, during a 60-min complete occlusion of the circumflex coronary artery, and during a 2-h reperfusion period. Blood pressure, heart rate, left anterior descending artery flow, and associated myocardial oxygen consumption were unaffected by acute pre-treatment with canagliflozin or cariporide during ischemia and reperfusion. Acute pre-ischemic treatment with canagliflozin significantly increased diastolic filling and stroke work, producing a rightward shift in the Frank-Starling relationship, and also improved cardiac work efficiency relative to untreated control hearts during ischemia. Effects of NHE-1 inhibition with cariporide were modest and dissimilar. Examination of AP-1 cells transfected with wild-type NHE-1 and iPSC-derived cardiomyocytes confirmed dose-dependent-inhibition of NHE-1 activity by cariporide, while canagliflozin had no significant effect on NHE-1 activity. ConclusionAcute pre-treatment with SGLT2i produces cardioprotective effects during ischemia, including improved work efficiency. These effects are not explained by NHE-1 inhibition. Translational perspectiveSGLT2 inhibitors have been shown to improve cardiac outcomes in patient including reducing myocardial infarction incidence and mortality. The mechanism(s) explaining this effect are not clear. This manuscript demonstrates a protective effect from acute SGLT2i exposure, as short as 15 min, prior to experimental infarction in swine. These effects were independent of NHE1 inhibition. These observations suggest that SGLT2 inhibitors can confer cardioprotective effects on a very short time scale. It is possible that such effects provide an ongoing contribution to ischemic protection even in the setting of chronic treatment.

Extraction of Pectin from Orange Peel and Study of Its Protective Effect Against Loperamide-Induced Impaired Gastrointestinal Motor Functions and Oxidative Stress in Rats.

Pectin is a polysaccharide attached to carbohydrates. These are substances exclusively of plant origin. The aim of the present study is to evaluate the laxative effects of orange peel pectin extract (OPPE) against constipation induced by loperamide (LOP) in rats. Rats were equally divided into six groups and treated daily 1 week as follows: Control, LOP (3 mg/kg, body weight [b.w.], Per Os [p.o.]), LOP+yohimbine (2 mg/kg, b.w., i.p.), and LOP+OPPE (6.25, 12.5, and 25 mg/kg, b.w., p.o.). At the end of the experiment, the effects of OPPE were assessed by fecal parameters (numbers, weight, and water content), gastrointestinal transit, gastric emptying, serum metabolic parameter changes, intestinal and colon mucosa oxidative stress, and the histological examination. The defecation test showed that administration of LOP (3 mg/kg, b.w., p.o.) leads to the production of remarkable constipation. Indeed, the number and water content of stools decreased (25.50 [n/24 h] and 29.86%) significantly (P < .05). Acute pretreatment with OPPE significantly and dose dependently accelerated the stool moistening and allowed an increase of stool weight (2.85, 3.61, 3.93 [g/24 h/rat]) as well as the frequency of defecation (47.36, 54.54, and 56.26 [n/24 h]). OPPE also significantly (P < .05) and dose dependently increased the intestinal motility (70.78%, 73.33%, and 75.01%) and gastric emptying. LOP-induced reduction (P < .05) of intestinal secretion was accompanied by a colonic and small bowel oxidative stress status and histological changes, which was attenuated by OPPE treatment. The findings of this study indicate that OPPE possesses an important role in the gastrointestinal motility regulation, and thus lend pharmacological credence to the suggested use of the natural pectin for the treatment, management, and/or control of constipation.

An ontogenic study of receptor mechanisms by which acute administration of low-doses of methamphetamine suppresses DOI-induced 5-HT2A-receptor mediated head-twitch response in mice

BackgroundMethamphetamine (MA) is a non-selective monoamine releaser and thus releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) from corresponding nerve terminals into synapses. DOI ((±)-2, 5-dimethoxy-4-iodoamphetamine) is a direct-acting serotonergic 5-HT2A/C receptor agonist and induces the head-twitch response (HTR) via stimulation of 5-HT2A receptor in mice. While more selective serotonin releasers such as d-fenfluramine evoke the HTR, monoamine reuptake blockers (e.g., cocaine) suppress the DOI-evoked HTR via indirect stimulation of serotonergic 5-HT1A- and adrenergic ɑ2-receptors. Since the induction of HTR by DOI is age-dependent, we investigated whether: (1) during development MA can evoke the HTR by itself, and (2) acute pretreatment with either the selective 5-HT2A receptor antagonist EMD 281014 or low-doses of MA can: (i) modulate the DOI-induced HTR in mice across postnatal days 20, 30 and 60, and (ii) alter the DOI-induced c-fos expression in mice prefrontal cortex (PFC). To further explore the possible modulatory effect of MA on DOI-induced HTR, we investigated whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors by corresponding selective antagonists (WAY 100635 or RS 79948, respectively), can prevent the effect of MA on DOI-induced HTR during aging.ResultsAlthough neither EMD 281014 nor MA by themselves could evoke the HTR, acute pretreatment with either EMD 281014 (0.01, 0.05 and 0.1 mg/kg, i.p.) or MA (1, 2.5, 5 mg/kg, i.p.), dose-dependently suppressed the DOI-induced HTR across ages. While WAY 100635 significantly reversed the inhibitory effect of MA in 20- and 30-day old mice, RS 79948 failed to significantly counter MA’s inhibitory effect. Moreover, DOI significantly increased c-fos expressions in several PFC regions. EMD 281014 prevented the DOI-induced increases in c-fos expression. Despite the inhibitory effect of MA on DOI-induced HTR, MA alone or in combination with DOI, significantly increased c-fos expression in several regions of the PFC.ConclusionThe suppressive effect of MA on the DOI-evoked HTR appears to be mainly due to functional interactions between the HTR-inducing 5-HT2A receptor and the inhibitory 5-HT1A receptor. The MA-induced increase in c-fos expression in different PFC regions may be due to MA-evoked increases in synaptic concentrations of 5-HT, NE and/or DA.

Therapeutic Effects of Hydroalcoholic Extracts from the Ancient Apple Mela Rosa dei Monti Sibillini in Transient Global Ischemia in Rats.

The Mela Rosa dei Monti Sibillini is an ancient apple variety cultivated by Romans in the foothills of the Sibillini Mountains, central Italy, showing potential as a source of nutraceuticals. The purpose of this study was to evaluate the protective effects of the hydroalcoholic extracts from the peel (APE) and pulp (APP) of this fruit in an animal model of transient global ischemia. Chemical constituents were analyzed by liquid chromatography–mass spectrometry (LC-DAD-MSn) indicating several polyphenols such as B-type procyanidins, quercetin derivatives and hydroxycinnamic acids as the main bioactive components. Acute pre-treatment of extracts (30 mg/kg, i.p.) significantly decreased the brain levels of the pro-inflammatory cytokines IL-1β (p < 0.01) and TNF-α (p < 0.001 and p < 0.01 for APE and APP, respectively), the expression of caspase-3 (p < 0.01, For APE) and MDA (p < 0.05), a lipid peroxidation biomarker in rats. Both extracts restricted the pathological changes of the brain induced by ischemic stroke in hematoxylin and eosin assay. Moreover, they improved the scores of behavioral tests in grid-walking and modified neurological severity scores (mNSS) tests. In conclusion, these results proved this ancient Italian apple is a source of nutraceuticals able to protect/prevent damage from brain ischemia.

Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains.

Cyclic AMP (cAMP)-dependent signaling is highly implicated in the pathophysiology of alcohol use disorder (AUD), with evidence supporting the efficacy of inhibiting the cAMP hydrolyzing enzyme phosphodiesterase 4 (PDE4) as a therapeutic strategy for drinking reduction. Off-target emetic effects associated with non-selective PDE4 inhibitors has prompted the development of selective PDE4 isozyme inhibitors for treating neuropsychiatric conditions. Herein, we examined the effect of a selective PDE4B inhibitor A33 (0–1.0 mg/kg) on alcohol drinking in both female and male mice from two genetically distinct C57BL/6 substrains. Under two different binge-drinking procedures, A33 pretreatment reduced alcohol intake in male and female mice of both substrains. In both drinking studies, there was no evidence for carry-over effects the next day; however, we did observe some sign of tolerance to A33’s effect on alcohol intake upon repeated, intermittent, treatment (5 injections of 1.0 mg/kg, every other day). Pretreatment with 1.0 mg/kg of A33 augmented sucrose intake by C57BL/6NJ, but not C57BL/6J, mice. In mice with a prior history of A33 pretreatment during alcohol-drinking, A33 (1.0 mg/kg) did not alter spontaneous locomotor activity or basal motor coordination, nor did it alter alcohol’s effects on motor activity, coordination or sedation. In a distinct cohort of alcohol-naïve mice, acute pretreatment with 1.0 mg/kg of A33 did not alter motor performance on a rotarod and reduced sensitivity to the acute intoxicating effects of alcohol. These data provide the first evidence that selective PDE4B inhibition is an effective strategy for reducing excessive alcohol intake in murine models of binge drinking, with minimal off-target effects. Despite reducing sensitivity to acute alcohol intoxication, PDE4B inhibition reduces binge alcohol drinking, without influencing behavioral sensitivity to alcohol in alcohol-experienced mice. Furthermore, A33 is equally effective in males and females and exerts a quantitatively similar reduction in alcohol intake in mice with a genetic predisposition for high versus moderate alcohol preference. Such findings further support the safety and potential clinical utility of targeting PDE4 for treating AUD.

Nalmefene, a mu opioid receptor antagonist/kappa opioid receptor partial agonist, potentiates cocaine motivation but not intake with extended access self-administration in adult male mice

The mu opioid receptor antagonist/kappa opioid receptor (KOR) partial agonist nalmefene (NMF), a close structural analog of naltrexone (NTX), has been shown to reduce cocaine reward in preclinical models. Given the greater KOR potency and improved bioavailability compared to NTX, NMF may be a promising pharmacotherapeutic for cocaine use disorder (CUD). Here we examine the effects of NMF pretreatment on chronic daily extended access (4h) cocaine intravenous self-administration (IVSA) in adult male C57Bl/6J mice. Methods: separate groups of mice had daily 4h cocaine IVSA sessions (0.25 or 0.5 mg/kg/inf, FR1) for 14 days. Starting on day 8, mice were pretreated with NMF (0, 1, or 10 mg/kg) 30m before each session. A separate group of mice acquired cocaine IVSA [seven days FR1 then four FR3 of 4h daily sessions (0.5 mg/kg/inf)] prior to a single progressive ratio 3 session to examine the effect of 1 mg/kg NMF on cocaine motivation. Results: No significant effect of NMF pretreatment on cocaine intake was observed. Acute pretreatment of 1 mg/kg NMF significantly potentiated cocaine motivation as measured by progressive ratio breakpoint. Conclusions: NMF did not significantly attenuate cocaine intake and increased motivation for cocaine suggesting that NMF may not be suitable for non-abstinent CUD patients. Further research is needed with KOR selective partial or full agonists to determine their effect on cocaine reinforcement.

Isofuranodiene, a Natural Sesquiterpene Isolated from Wild Celery (Smyrnium olusatrum L.), Protects Rats against Acute Ischemic Stroke.

The myrrh-like furanosesquiterpene isofuranodiene (IFD) is the main constituent of wild celery (Smyrnium olusatrum L., Apiaceae), an overlooked vegetable that was cultivated during the Roman Empire. In the present study, we investigated the protective effects of IFD pre-treatment against oxidative stress and inflammatory response in an animal model of ischemic stroke. IFD was isolated by the crystallization of Smyrnium olusatrum essential oil, and its structure and purity were confirmed by NMR and HPLC analyses. Acute pre-treatment of IFD (10 mg/kg i.p.) significantly reduced the levels of the inflammatory cytokines IL-1β and TNF-α, the expression of pNF-κB/NF-κB, and the lipid peroxidation indicator MDA. Finally, IFD boosted a faster recovery and better scores in grid-walking and modified neurological severity scores (mNSS) tests. Taken together, these findings indicate IFD as a promising lead compound for the discovery of new treatments of brain ischemia.

Testing the effects of the GLP-1 receptor agonist exenatide on cocaine self-administration and subjective responses in humans with cocaine use disorder

BackgroundPreclinical rodent studies have demonstrated reduced cocaine taking after administration of glucagon-like peptide 1 (GLP-1) analogues. We investigated effects of a GLP-1 analogue (exenatide) on behavioral and subjective effects of cocaine in individuals with cocaine use disorder (CUD). MethodsNon-treatment-seeking CUD subjects underwent two human laboratory cocaine self-administration test sessions following an acute 3 -h pre-treatment with exenatide (5 mcg; subcutaneously) or placebo. Primary outcomes consisted of infusions of cocaine and visual analog scale self-ratings of euphoria and wanting cocaine. Secondary outcomes consisted of pertinent hormone levels (GLP-1, insulin, and amylin). ResultsThirteen individuals completed the study. Acute pretreatment with exenatide versus placebo did not change cocaine infusions (8.5 ± 1.2 vs. 9.1 ± 1.2; p = 0.39), self-reported euphoria (4.4 ± 0.8 vs. 4.1 ± 0.8; p = 0.21), or wanting of cocaine (5.6 ± 0.9 vs. 5.4 ± 0.9; p = 0.46). Exenatide vs. placebo reduced levels of GLP-1 (p = 0.03) and insulin (p = 0.02). Self-administered cocaine also reduced levels of GLP-1 (p < 0.0001), insulin (p < 0.0001), and amylin (p < 0.0001). ConclusionsWe did not find evidence that low dose exenatide alters cocaine self-administration or the subjective effects of cocaine in people with CUD. Limitations such as single acute rather than chronic pre-treatment, as well as evaluation of only one dose, preclude drawing firm conclusions about the efficacy of exenatide. Exenatide and cocaine independently reduced levels of GLP-1 and insulin, while cocaine also reduced levels of amylin.

Maternal separation increases pain sensitivity by reducing the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus

Animals subjected to early life maternal separation exhibit increased sensitivity to chemical, thermal, and mechanical stimuli during adulthood. However, the mechanism by which maternal separation can alter pain sensitivity in adulthood has not yet been investigated. Thus, we aimed to evaluate the activity of serotonergic and noradrenergic neurons and the effect of serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors in male and female Wistar rats subjected to maternal separation. This study consisted of two experiments: 1) to confirm whether maternal separation increased pain sensitivity (n = 8 per group) and to evaluate the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus in animals subjected to maternal separation in comparison to controls (n = 6 per group); and 2) to evaluate the effect of fluoxetine (a selective 5-HT reuptake inhibitor) and desipramine (a NA reuptake inhibitor) on sensitivity to chemical stimulation using formalin in animals subjected to maternal separation (n = 8 per group). Our findings indicated that maternal separation increases an animal’s sensitivity to painful chemical stimulation and reduces the activity of 5-HT and NA neurons. In addition, acute pretreatment with a 5-HT or NA reuptake inhibitor prevented the increased response to painful stimulation induced by maternal separation. In conclusion, maternal separation increases pain sensitivity by reducing the activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in locus coeruleus. This study contributes to possible treatments for pain in individuals exposed to early life stress.

High-Dose Atorvastatin Raises Threshold of Contrast-Induced Nephropathy in Diabetic Patients Undergoing Elective Coronary Intervention: A Randomized Controlled Study

Background. Contrast-induced nephropathy (CIN) is a significant complication of angiographic procedures resulting from injection of iodinated contrast media (CM). Patients with diabetes mellitus (DM) are at the highest risk of CIN. Statins have recently been proposed for protection against CIN due to their antioxidant and anti-inflammatory properties. Aim of Work. To investigate the potential benefit of acute pretreatment with high-dose atorvastatin (80 mg) in reduction of the incidence of CIN in diabetic patients indicated for elective coronary intervention. Patients and Methods. 200 diabetic patients with indication for coronary intervention were enrolled in the study. 100 patients will be randomly assigned to receive atorvastatin (80 mg) just before coronary intervention (statin group) and 100 patients received placebo (control group). CIN was defined as a rise of serum creatinine of more than 25% or ≥0.5 mg/dl (44 μmol/l) from baseline within 48 hours of the angiography. After the procedure, Thrombolysis in Myocardial Infarction (TIMI) flow of the culprit vessel was reported, as well as the volume of used contrast media and time of X-ray exposure. Results. Our study reported a CIN incidence of 12, 18, and 6% among the whole study, placebo, and statin groups, respectively, P value of 0.001. Among the placebo group, CIN is likely to develop after a 13.5-minute X-ray exposure time with a specificity of 73.2% and sensitivity of 77.8%, area under the curve (AUC) of 0.879 (CI: 0.798–0.960), and P value of 0.001, while in the statin group, CIN is likely to develop after 14.5-minute X-ray exposure time with a specificity of 74.5% and sensitivity of 83.3%, AUC of 0.818 (CI: 0.727–0.910), and P value of 0.009. In the placebo group, CIN is likely to develop after injection of 145 ml of contrast media with a specificity of 75.6% and sensitivity of 77.8%, AUC of 0.855 (CI: 0.757–0.952), and P value of 0.001, while in the statin group, CIN is likely to develop after injection of 165 ml of contrast media with a specificity of 84% and sensitivity of 83.3%, AUC of 0.878 (CI: 0.811–0.944), and P value of 0.002. Conclusions. Acute pretreatment with high-dose atorvastatin can effectively protect against CIN and was associated with a marked decrease in the prevalence of CIN in diabetic patients undergoing coronary interventions. Moreover, pretreatment with high-dose atorvastatin raises the threshold of X-ray exposure time and the amount of contrast media beyond which CIN is likely to develop. The trial is registered with NCT04375787.

Sevoflurane-induced hyperglycemia is attenuated by salsalate in obese insulin-resistant mice.

Perioperative hyperglycemia is common and is associated with significant morbidity. Although patient characteristics and surgery influence perioperative glucose metabolism, anesthetics have a significant impact. We hypothesized that mice that were obese and insulin-resistant would experience greater hyperglycemia in response to sevoflurane anesthesia compared with lean controls. We further hypothesized that sevoflurane-induced hyperglycemia would be attenuated by salsalate pre-treatment. Lean and obese male C57BL/6J mice were anesthetized with sevoflurane for 60 min with or without pre-treatment of 62.5 mg·kg-1 salsalate. Blood glucose, plasma insulin, and glucose uptake into different tissues were measured. Under sevoflurane anesthesia, obese mice had higher blood glucose compared to lean mice. Increases in blood glucose were attenuated with acute salsalate pre-treatment at 60 min under anesthesia in obese mice (mean ± standard error of the mean [SEM], delta blood glucose; vehicle 5.79 ± 1.09 vs salsalate 1.91 ± 1.32 mM; P = 0.04) but did not reach statistical significance in lean mice (delta blood glucose, vehicle 4.39 ± 0.55 vs salsalate 2.79 ± 0.71 mM; P = 0.10). This effect was independent of changes in insulin but associated with an approx. 1.7-fold increase in glucose uptake into brown adipose tissue (vehicle 45.28 ± 4.57 vs salsalate 76.89 ± 12.23 µmol·g-1 tissue·hr-1; P < 0.001). These data show that salsalate can reduce sevoflurane-induced hyperglycemia in mice. This indicates that salsalate may represent a new class of therapeutics that, in addition to its anti-inflammatory and analgesic properties, may be useful to reduce perioperative hyperglycemia.