oleylamide and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Topics: Animals; Anti-Obesity Agents; Antioxidants; Body Weight; Calorimetry, Differential Scanning; Capsaicin; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Drug Liberation; Endocannabinoids; Feeding Behavior; Kinetics; Lipids; Mice; Nanostructures; Obesity; Oleic Acids; Particle Size; Static Electricity; Temperature

A growing body of psychiatric research has emerged, focusing on the role of endocannabinoid system in psychiatric disorders. For example, the endocannabinoid system, via cannabinoid CB (CB1 and CB2) receptors, is able to control the function of many receptors, such as N-methyl-D-aspartate (NMDA) receptors connected strictly with psychosis or other schizophrenia-associated symptoms. The aim of the present research was to investigate the impact of the CB1 receptor ligands on the symptoms typical for schizophrenia. We provoked psychosis-like effects in mice by an acute administration of NMDA receptor antagonist, MK-801 (0.1-0.6 mg/kg). An acute administration of MK-801 induced psychotic symptoms, manifested in the increase in locomotor activity (hyperactivity), measured in actimeters, as well as the memory impairment, assessed in the passive avoidance task. We revealed that an acute injection of CB1 receptor agonist, oleamide (5-20 mg/kg), had no influence on the short- and long-term memory-related disturbances, as well as on the hyperlocomotion in mice, provoking by an acute MK-801. In turn, an amnestic effects or hyperactivity induced by an acute MK-801 was attenuated by an acute administration of AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist. The present findings confirm that endocannabinoid system is able to modify a variety of schizophrenia-like responses, including the cognitive disturbances and hyperlocomotion in mice. Antipsychotic-like effects induced by CB1 receptor antagonist, obtained in our research, confirm the potential effect of CB1 receptor blockade and could have important therapeutic implications on clinical settings, in the future.

Topics: Animals; Antipsychotic Agents; Cannabinoid Receptor Modulators; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Endocannabinoids; Excitatory Amino Acid Antagonists; Male; Memory Disorders; Memory, Long-Term; Memory, Short-Term; Mice; Motor Activity; Oleic Acids; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Schizophrenia; Schizophrenic Psychology

Depression is a complex psychiatric disorder, and its etiology and pathophysiology are not completely understood. Depression involves changes in many biogenic amine, neuropeptide, and oxidative systems, as well as alterations in neuroendocrine function and immune-inflammatory pathways. Oleamide is a fatty amide which exhibits pharmacological effects leading to hypnosis, sedation, and anti-anxiety effects. In the present study, the chronic mild stress (CMS) model was used to investigate the antidepressant-like activity of oleamide. Rats were exposed to 10weeks of CMS or control conditions and were then subsequently treated with 2weeks of daily oleamide (5mg/kg, i.p.), fluoxetine (10mg/kg, i.p.), or vehicle. Protein extracts from the hippocampus were then collected, and hippocampal maps were generated by way of two-dimensional gel electrophoresis (2-DE). Altered proteins induced by CMS and oleamide were identified through mass spectrometry and database searches. Compared to the control group, the CMS rats exhibited significantly less body weight gain and decreased sucrose consumption. Treatment with oleamide caused a reversal of the CMS-induced deficit in sucrose consumption. In the proteomic analysis, 12 protein spots were selected and identified. CMS increased the levels of adenylate kinase isoenzyme 1 (AK1), nucleoside diphosphate kinase B (NDKB), histidine triad nucleotide-binding protein 1 (HINT1), acyl-protein thioesterase 2 (APT-2), and glutathione S-transferase A4 (GSTA4). Compared to the CMS samples, seven spots changed significantly following treatment with oleamide, including GSTA4, glutathione S-transferase A6 (GSTA6), GTP-binding nuclear protein Ran (Ran-GTP), ATP synthase subunit d, transgelin-3, small ubiquitin-related modifier 2 (SUMO2), and eukaryotic translation initiation factor 5A-1 (eIF5A1). Of these seven proteins, the level of eIF5A1 was up-regulated, whereas the remaining proteins were down-regulated. In conclusion, oleamide has antidepressant-like properties in the CMS rat model. The identification of proteins altered by CMS and oleamide treatment provides support for targeting these proteins in the development of novel therapies for depression.

Topics: Animals; Antidepressive Agents; Biomarkers; Depression; Disease Models, Animal; Electrophoresis, Gel, Two-Dimensional; Fluoxetine; Hippocampus; Male; Nerve Tissue Proteins; Oleic Acids; Proteomics; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Stress, Psychological

The purpose of the experiments was to explore the role of the endocannabinoid system, through cannabinoid (CB) receptor ligands, nicotine and scopolamine, in the depression-related responses using the forced swimming test (FST) in mice. Our results revealed that acute injection of oleamide (10 and 20 mg/kg), a CB1 receptor agonist, caused antidepressant-like effect in the FST, while AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist, did not provoke any effect in this test. Moreover, acute administration of both CB2 receptor agonist, JWH 133 (0.5 and 1 mg/kg) and CB2 receptor antagonist, AM 630 (0.5 mg/kg), exhibited antidepressant action. Antidepressant effects of oleamide and JWH 133 were attenuated by acute injection of both non-effective dose of AM 251, as well as AM 630. Among the all CB compounds used, only the combination of non-effective dose of oleamide (2.5 mg/kg) with non-effective dose of nicotine (0.5 mg/kg) caused an antidepressant effect. However, none of the CB receptor ligands, had influence on the antidepressant effects provoked by nicotine (0.2 mg/kg) injection. In turn, the combination of non-effective dose of oleamide (2.5 mg/kg); JWH (2 mg/kg) or AM 630 (2 mg/kg), but not of AM 251 (0.25 mg/kg), with non-effective dose of scopolamine (0.1 mg/kg), exhibited antidepressant properties. Indeed, all of the CB compounds used, intensified the antidepressant-like effects induced by an acute injection of scopolamine (0.3 mg/kg). Our results provide clear evidence that the endocannabinoid system participates in the depression-related behavior and through interactions with cholinergic system modulate these kind of responses.

Topics: Animals; Antidepressive Agents; Cannabinoids; Depressive Disorder; Disease Models, Animal; Indoles; Ligands; Male; Mice; Motor Activity; Nicotine; Oleic Acids; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Scopolamine; Swimming

The unusual hypolipidemic activity of the methanolic fractionate of the essential oil (EOM) obtained from the mountain celery seed was previously reported. The most enriched 9(Z)-octadecenamide (oleamide) was speculated to be responsible for the relevant bioactivity. Chemically syntheized oleamide (CSO) yielded 85.1% with a purity of 98.6% when identified by RP-HPLC, FTIR, HREIMS, (1)H NMR, and (13)C NMR. CSO was tested for its antioxidative and hypolipidemic bioactivities. Results indicated CSO was potently hypolipidemic with regard to serum TG, TC, LDL-C, LDL-C/HDL-C, and hepatic TG (p < 0.05), but not for serum HDL-C and hepatic TC. In addition, CSO exhibited only poor antioxidative activity, implicating the possibility that the hypolipidemic and antioxidative bioactivity of original EOM was due to another coexisting constituent, probably gamma-selinene. Conclusively, oleamide is a potent hypolipidemic agent as regarding its effects on decreasing serum TG, TC, LDL-C and hepatic TG.

Topics: Animals; Apium; Cricetinae; Disease Models, Animal; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipid Metabolism; Male; Mesocricetus; Oils, Volatile; Oleic Acids; Plant Oils; Random Allocation; Seeds

While it has long been recognized that Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, and other cannabinoid receptor agonists possess anti-inflammatory properties, their well known CNS effects have dampened enthusiasm for therapeutic development. On the other hand, genetic deletion of fatty acid amide hydrolase (FAAH), the enzyme responsible for degradation of fatty acid amides, including endogenous cannabinoid N-arachidonoyl ethanolamine (anandamide; AEA), N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA), and oleamide, also elicits anti-edema, but does not produce any apparent cannabinoid effects. The purpose of the present study was to investigate whether exogenous administration of FAAs would augment the anti-inflammatory phenotype of FAAH (-/-) mice in the carrageenan model. Thus, we evaluated the effects of the FAAs AEA, PEA, OEA, and oleamide in wild-type and FAAH (-/-) mice. For comparison, we evaluated the anti-edema effects of THC, dexamethasone (DEX), a synthetic glucocorticoid, diclofenac (DIC), a nonselective cyclooxygenase (COX) inhibitor, in both genotypes. A final study determined if tolerance to the anti-edema effects of PEA occurs after repeated dosing. PEA, THC, DEX, DIC elicited significant decreases in carrageenan-induced paw edema in wild-type mice. In contrast OEA produced a less reliable anti-edema effect than these other drugs, and AEA and oleamide failed to produce any significant decreases in paw edema. Moreover, none of the agents evaluated augmented the anti-edema phenotype of FAAH (-/-) mice, suggesting that maximal anti-edema effects had already been established. PEA was the most effective FAA in preventing paw edema and its effects did not undergo tolerance. While the present findings do not support a role for AEA in preventing carrageenan-induced edema, PEA administration and FAAH blockade elicited anti-edema effects of an equivalent magnitude as produced by THC, DEX, and DIC in this assay.

Topics: Amidohydrolases; Analysis of Variance; Animals; Arachidonic Acids; Cannabinoids; Carrageenan; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Interactions; Edema; Endocannabinoids; Ethanolamines; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Oleic Acids; Polyunsaturated Alkamides

Oleamide (cis-9,10-octadecenoamide) is an endogenous sleep-inducing lipid and prototypic member of a new class of biological signaling molecules identified in recent years. In the present study, the anxiolytic-like effect of oleamide was studied in several experimental models of anxiety in group-housed and socially isolated mice. As the results show, socially isolated mice exhibited an anxiogenic-like profile in the elevated plus-maze test, the light/dark test, and the hole-board test, which could be significantly reversed by oleamide (10 or 20 mg/kg, i.p.). Moreover, oleamide significantly reduced the anxiety levels in grouped-housed mice. In the isolation-induced aggressive test, oleamide markedly reduced the attacking duration and increased the attacking latency. It is concluded that oleamide has an anxiolytic-like effect in socially isolated or group-housed mice, which suggests that fatty acid amides might be involved in the regulation of anxiety-related behavior in mice.

Topics: Aggression; Analysis of Variance; Animals; Anxiety; Behavior, Animal; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Hypnotics and Sedatives; Male; Maze Learning; Mice; Oleic Acids; Reaction Time; Social Isolation; Stress, Psychological

Wound healing, a coordinated process, proceeds by sequential changes in cell differentiation and terminates with the deposition of a new connective tissue matrix, a scar. Initially, there is the migratory fibroblast, followed by the proliferative fibroblast, then the synthetic fibroblast, which transforms into the myofibroblast, and finally the apoptotic fibroblast. Gap junction intercellular communications are proposed to coordinate the stringent control of fibroblast phenotypic changes. Does added oleamide, a natural fatty acid that blocks gap junction intercellular communications, alter the phenotypic progression of wound fibroblasts?. Pairs of polyvinyl alcohol sponges attached to Alzet pumps, which constantly pumped either oleamide or vehicle solvent, were implanted subcutaneously into three rats. On day 8, implants were harvested and evaluated histologically and biochemically.. The capsule of oleamide-treated sponge contained closely packed fibroblasts with little connective tissue between them. The birefringence intensity of that connective tissue was reduced, indicating a reduced density of collagen fiber bundles. Myofibroblasts, identified immunohistologically by alpha-smooth muscle actin-stained stress fibers, were reduced in oleamide-treated implants. Western blot analysis showing less alpha-smooth muscle actin confirmed the reduced density of myofibroblasts.. It appears that oleamide retards the progression of wound repair, where less connective tissue is deposited, the collagen is less organized, and the appearance of myofibroblasts is impaired. These findings support the hypothesis that gap junction intercellular communications between wound fibroblasts in granulation tissue play a role in the progression of repair and the maturation of granulation tissue into scar.

Topics: Animals; Blotting, Western; Cell Communication; Disease Models, Animal; Fibroblasts; Fluorescent Antibody Technique; Gap Junctions; Granulation Tissue; Immunohistochemistry; Male; Oleic Acids; Rats; Rats, Sprague-Dawley; Reference Values; Risk Factors; Sensitivity and Specificity; Wound Healing; Wounds and Injuries

Gap junctions assemble astrocytes into syncytia, allowing exchange of metabolites, catabolites, and second-messenger molecules. Connexin43 is the predominant connexin of astrocytic gap junctions. The distribution of gap junction protein connexin43 was analyzed in different subfields of the hippocampal formation as a function of time after transient forebrain ischemia. One decisive key step in understanding why an ischemic insult gradually expands may be to establish how gap junction channels permit dying cells in the ischemic focus to communicate, in particular, with viable cells. The role of gap junctional intercellular communication in the hippocampus under ischemic conditions could be decisive for cell death propagation. We found that the vulnerable CA1/CA2 subfields have a higher density of gap junctions than the resistant CA3/CA4 areas, that changes in the distribution of connexin43 immunoreactivity may correlate with the phenomenon of selective vulnerability, and that inhibition of astrocytic gap junction permeability by octanol restricts the flow of undesirable neurotoxins that could potentially exacerbate neuronal damage. This provides a novel perspective for analysis of the pathophysiology of cerebral ischemia.

Topics: Animals; Cell Communication; Cell Death; Connexin 43; Disease Models, Animal; Gap Junctions; Glial Fibrillary Acidic Protein; Halothane; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Octanols; Oleic Acids; Pyramidal Cells; Rats; Rats, Wistar; Time Factors