Antinociceptive and anti-inflammatory effects of hydrazone derivatives and their possible mechanism of action in mice.

Pain and inflammation are unpleasant experiences that usually occur as a result of tissue damage. Despite the number of existing analgesic drugs, side effects limit their use, stimulating the search for new therapeutic agents. In this sense, five hydrazone derivatives (H1, H2, H3, H4, and H5), with general structure R1R2C = NNR3R4, were synthesized with molecular modification strategies. In this paper, we describe the ability of hydrazone derivatives to attenuate nociceptive behavior and the inflammatory response in mice. Antinociceptive activity was evaluated through acetic acid-induced writhing and formalin-induced nociception tests. In both experimental models, the hydrazone with the greatest potency (H5) significantly (p < 0.05) reduced nociceptive behavior. Additionally, methods of acute and chronic inflammation induced by different chemicals (carrageenan and histamine) were performed to evaluate the anti-inflammatory effect of H5. Moreover, molecular docking analysis revealed that H5 can block the COX-2 enzyme, reducing arachidonic acid metabolism and consequently decreasing the production of prostaglandins, which are important inflammatory mediators. H5 also changes locomotor activity. In summary, H5 exhibited relevant antinociceptive and anti-inflammatory potential and acted on several targets, making it a candidate for a new multi-target oral anti-inflammatory drug.

Evaluation of the In Vivo Acute Toxicity and In Vitro Hemolytic and Immunomodulatory Activities of the Moringa oleifera Flower Trypsin Inhibitor (MoFTI).

BACKGROUND: Protease inhibitors have been isolated from plants and present several biological activities, including immunomodulatory action. OBJECTIVE: This work aimed to evaluate a Moringa oleifera flower trypsin inhibitor (MoFTI) for acute toxicity in mice, hemolytic activity on mice erythrocytes and immunomodulatory effects on mice splenocytes. METHODS: The acute toxicity was evaluated using Swiss female mice that received a single dose of the vehicle control or MoFTI (300 mg/kg, i.p.). Behavioral alterations were observed 15-240 min after administration, and survival, weight gain, and water and food consumption were analyzed daily. Organ weights and hematological parameters were analyzed after 14 days. Hemolytic activity of MoFTI was tested using Swiss female mice erythrocytes. Splenocytes obtained from BALB/c mice were cultured in the absence or presence of MoFTI for the evaluation of cell viability and proliferation. Mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) levels were also determined. Furthermore, the culture supernatants were analyzed for the presence of cytokines and nitric oxide (NO). RESULTS: MoFTI did not cause death or any adverse effects on the mice except for abdominal contortions at 15-30 min after administration. MoFTI did not exhibit a significant hemolytic effect. In addition, MoFTI did not induce apoptosis or necrosis in splenocytes and had no effect on cell proliferation. Increases in cytosolic and mitochondrial ROS release, as well as Δψm reduction, were observed in MoFTI-treated cells. MoFTI was observed to induce TNF-α, IFN-γ, IL-6, IL-10, and NO release. CONCLUSION: These results contribute to the ongoing evaluation of the antitumor potential of MoFTI and its effects on other immunological targets.

Antitumor activity of Moringa oleifera (drumstick tree) flower trypsin inhibitor (MoFTI) in sarcoma 180-bearing mice.

The plant Moringa oleifera is used as food and medicine. M. oleifera flowers are source of protein, fiber, and antioxidants, and are used to treat inflammation and tumors. This work evaluated the antitumor activity of the M. oleifera flower trypsin inhibitor (MoFTI) in sarcoma 180-bearing mice. Swiss female mice were inoculated with sarcoma 180 cells. Seven days later, the animals were treated intraperitoneally for 1 week with daily doses of PBS (control) or MoFTI (15 or 30 mg/kg). For toxicity assessment, water and food consumption, body and organ weights, histological alterations, and blood hematological and biochemical parameters were measured. Treatment with MoFTI caused pronounced reduction (90.1%-97.9%) in tumor weight. The tumors of treated animals had a reduced number of secondary vessels and lower gauge of the primary vessels compared to the control. No significant changes were observed in water and food consumption or in body and organ weights. Histopathological analysis did not indicate damage to the liver, kidneys, and spleen. In conclusion, MoFTI showed antitumor potential, with no clear evidence of toxicity.

Anticonvulsant, sedative, anxiolytic and antidepressant activities of the essential oil of Annona vepretorum in mice: Involvement of GABAergic and serotonergic systems.

Annona vepretorum is an endemic species of the Caatinga biome, known in Northeastern Brazil as "araticum" and/or "pinha da Caatinga". In the present study it was evaluated the neuropharmacological potential of the essential oil obtained from the leaves of Annona vepretorum, as well as of the inclusion complexes of oil obtained with cyclodextrin. Thus, were used neuropharmacological tests already consolidated in the literature like open-field, elevated plus maze, rota-rod, tail suspension test, thiopental-induced sleep test, among others. The acute treatment of essential oil (EO) has anxiolytic, sedative, antiepileptic and antidepressant effects. The anxiolytic and anticonvulsant effects seems to be related to the GABAergic system, probably in the receptor subtypes that mediate the effects of the benzodiazepines, to generate anxiolytic activity. The sedative effect seems to be involved with other signaling pathways. The antidepressant effect of EO seems to be related to its action on serotonergic receptors. It was verified that some behavioral parameters were improved with the oil complexed with ß-cyclodextrin, but this effect was not uniform for all the doses and tests used. Further studies are needed in order to use other options for drug delivery systems. Thus, the essential oil of Annona vepretorum is a promising agent with neurobiological activity and a potential target for drug discovery, since the natural products such as medicinal plants have been a source of new therapeutic proposals.

Ethanolic extract of the aerial parts of Passiflora cincinnata Mast. (Passifloraceae) reduces nociceptive and inflammatory events in mice.

BACKGROUND: Passiflora cincinnata Mast. is described as a native species from the Caatinga biome, and used by traditional medicine for several pharmacological purposes, such as inflammatory disorders. However, studies that prove its biological activities are scarce. HYPOTHESIS/PURPOSE: This paper aims to evaluate the antinociceptive and anti-inflammatory activities of the aerial parts of Passiflora cincinnata (Pc-EtOH) in mice. METHODS: The chemical composition of Pc-EtOH was assessed by high-performance liquid chromatography coupled to diode array detector (HPLC-DAD). The antinociceptive profile of the extract (given orally: 100, 200 and 400 mg/kg) was established using the in vivo chemical models (acetic acid-induced abdominal constriction and formalin-induced paw licking test) and thermal (hot plate test) of nociception. The role of opioid, potassium channels, TRPV-1, muscarinic, serotoninergic (5-HT3) receptors and the participation of the nitric oxide pathway also was determined. The rota-rod test was used to verify the possible interference of the extract treatment in motor performance. Paw edema induced by carrageenan or histamine, and leukocyte migration, determination of total protein and nitric oxide to the peritoneal cavity were used for anti-inflammatory profile. RESULTS: The presence of flavonoids in the extract was confirmed using HPLC-DAD. At all doses tested the Pc-EtOH significantly reduced the number of writhing and decreased the paw licking time in both phases of the formalin test (p < 0.05). In the hot plate test, the extract increased the reaction time, reducing painful behavior. The antinociceptive mechanism probably involves central and peripheral pathways, involving the pathway of opioid and muscarinic receptors with influence of potassium channels and the nitric oxide pathway. However, the motor coordination test indicated that in the time of 120 min the extract decreases the stay time of the animal in the rota-rod. Pc-EtOH inhibited significantly (p < 0.05) the increase of the edema volume after administration of carrageenan and histamine. In the peritonitis test, acute pre-treatment with Pc-EtOH inhibited leukocyte migration, with a reduction in the number of neutrophils and concentration of total proteins and nitric oxide. CONCLUSION: The present study suggests that Pc-EtOH possesses peripheral and central antinociceptive action, and showed potential in inhibition of release of mediators of the inflammatory process.

Flavonoids as Therapeutic Agents in Alzheimer's and Parkinson's Diseases: A Systematic Review of Preclinical Evidences.

Alzheimer's and Parkinson's diseases are considered the most common neurodegenerative disorders, representing a major focus of neuroscience research to understanding the cellular alterations and pathophysiological mechanisms involved. Several natural products, including flavonoids, are considered able to cross the blood-brain barrier and are known for their central nervous system-related activity. Therefore, studies are being conducted with these chemical constituents to analyze their activities in slowing down the progression of neurodegenerative diseases. The present systematic review summarizes the pharmacological effects of flavonoids in animal models for Alzheimer's and Parkinson's diseases. A PRISMA model for systematic review was utilized for this search. The research was conducted in the following databases: PubMed, Web of Science, BIREME, and Science Direct. Based on the inclusion criteria, 31 articles were selected and discussed in this review. The studies listed revealed that the main targets of action for Alzheimer's disease therapy were reduction of reactive oxygen species and amyloid beta-protein production, while for Parkinson's disease reduction of the cellular oxidative potential and the activation of mechanisms of neuronal death. Results showed that a variety of flavonoids is being studied and can be promising for the development of new drugs to treat neurodegenerative diseases. Moreover, it was possible to verify that there is a lack of translational research and clinical evidence of these promising compounds.

Essential Oils and Their Major Compounds in the Treatment of Chronic Inflammation: A Review of Antioxidant Potential in Preclinical Studies and Molecular Mechanisms.

Inflammatory diseases result from the body's response to tissue damage, and if the resolution is not adequate or the stimulus persists, there will be progression from acute inflammation to chronic inflammation, leading to the development of cancer and neurodegenerative and autoimmune diseases. Due to the complexity of events that occur in inflammation associated with the adverse effects of drugs used in clinical practice, it is necessary to search for new biologically active compounds with anti-inflammatory activity. Among natural products, essential oils (EOs) present promising results in preclinical studies, with action in the main mechanisms involved in the pathology of inflammation. The present systematic review summarizes the pharmacological effects of EOs and their compounds in in vitro and in vivo models for inflammation. The research was conducted in the following databases: PubMed, Scopus, BIREME, Scielo, Open Grey, and Science Direct. Based on the inclusion criteria, 30 articles were selected and discussed in this review. The studies listed revealed a potential activity of EOs and their compounds for the treatment of inflammatory diseases, especially in chronic inflammatory conditions, with the main mechanism involving reduction of reactive oxygen and nitrogen species associated with an elevation of antioxidant enzymes as well as the reduction of the nuclear factor kappa B (NF-κB), reducing the expression of proinflammatory cytokines. Thus, this review suggests that EOs and their major compounds are promising tools for the treatment of chronic inflammation.