Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 20, Issue 3, 2021

Background: A large amount of evidence has described that asthma may be associated with a high epilepsy risk, and epilepsy may be linked with high asthma risk, especially among children and individuals in their 30s. Curiously, asthma has also been associated with an increased risk for schizophrenia. Most interestingly, a bidirectional link between schizophrenia and epilepsy has also been established and has been of interest for many years. Objective: Bearing in mind the experience of our group in the field of Ca²⁺/cAMP signalling pathways, this article discussed, beyond inflammation, the role of these signalling pathways in this link among epilepsy, asthma, and schizophrenia. Methods: Publications involving these signalling pathways, asthma, epilepsy, and schizophrenia (alone or combined) were collected by searching PubMed and EMBASE. Results and Conclusion: There is a clear relationship between Ca²⁺ signalling, e.g. increased Ca²⁺ signals and inflammatory responses. In addition to Ca²⁺, cAMP regulates pro- and anti-inflammatory responses. Then, beyond inflammation, the comprehension of the link among epilepsy, asthma, and schizophrenia could improve the drug therapy.

Background: For the first time, the inhibitory effects on the human salivary alpha-amylase activity of the anti-inflammatory drugs indomethacin, diclofenac sodium, ketoprofen, diclofenac potassium, diclofenac, triamcinolone acetonide, and the antihistamine drugs levocetirizine dihydrochloride, desloratadine, cycloheptadine hydrochloride, have been investigated to confirm the other properties of these drugs. Objective: This study aimed to determine the effect of nine known drugs on human salivary α-amylase in vitro and the nature of interactions with structure-activity relationship using molecular docking experiments. Methods: The inhibition of human salivary alpha amylase by the six anti-inflammatory and three antihistamine drugs has been carried out using the new method that has been proved in our previous work. Molecular docking has been achieved for the first time for these drugs using the Auto- Dock Vina program. Results: Cyproheptadine hydrochloride presented the highest inhibitory activity against α-amylase with IC50=0.7 mg/ml, while the other drugs showed weak activities (IC50 > 2 mg/ml). Conclusion: We conclude that Cyproheptadine hydrochloride, which was studied by docking experiments, exhibited the best inhibitory activity on salivary α-amylase in vitro & in silico.

Background: Oleanolic acid (OA) is a naturally occurring pentacyclic triterpenoid with multifarious actions. The anti-inflammatory effect it exerts when taken orally is the most important; however, the underpinning mechanisms of such effects have not yet been fully explored. Methods: In the present study, we evaluated the anti-inflammatory and anti-nociceptive effect of OA by injecting it directly into the knee joint using an animal model of osteoarthritis. Behavioral and electrophysiological studies were conducted to determine whether OA exerts a direct modulatory effect on primary sensory afferents that can lead to a decrease in pain-related behaviors and inflammatory responses. Rats were divided into two main groups: a pre- and a post-treatment group. Knee joint inflammation was induced by injecting a mixture of 3% kaolin and carrageenan (K/C). In the pre-treatment group, two different doses of OA [5 mg/ml (n=5) and 30 mg/ml (n=4); 0.1 ml per injection] were administered into the synovial cavity of the knee joint before induction of inflammation. In the post-treatment group, rats received only one dose [5 mg/ml (n=5)] of OA after induction of inflammation. Results: Results indicate that intra-articular injection of OA improves motor coordination and attenuates nociceptive behavior and inflammatory reactions. More importantly, we observed a direct depolarizing action of OA on articular sensory fibers, a crucial mechanism that activates descending inhibitory pathways and controls incoming nociceptive signals to the spinal cord. Conclusion: Overall, our findings suggest that OA can be used as a preventive and therapeutic approach for the management of osteoarthritis.

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disease manifested by core symptoms of loss of motor control and postural instability. Loss of dopaminergic neurons is the cause of PD, thus enhancing dopamine level by pharmacological treatment is one of the key treatment strategies for PD. However, the limitations of current treatment strategies open the possibility of novel drug candidates for the treatment of PD. Objective: To investigate the anti-PD potential of Harmine and Harmaline. We aim to evaluate the therapeutic potential of Harmine and Harmaline by in-silico approaches; molecular docking, pharmacokinetic and Prediction of Activity Spectra for Substances (PASS) analysis were used for evaluating the therapeutic potential of Harmine and Harmaline and standard drug levodopa (L-DOPA). Methods: Auto dock vina was used for molecular docking of all three compounds against D2- and D3- dopamine receptors. The pharmacokinetics (PKs) and toxicity profile were predicted by pkCSM, and the pharmacological activity was predicted by PASS analysis. Results: Molecular docking showed a higher binding affinity of Harmine and Harmaline as compared to L-DOPA, and these results were supported by in-silico pharmacokinetic and toxicity profiling. Moreover, PASS analysis showed anti-PD activity of Harmine and Harmaline. Conclusion: Harmine and Harmaline exhibit higher binding affinity towards D2- and D3- dopamine receptors compared to L-DOPA, and PKs and toxicity profile support their potential as drug candidates for PD therapy.

Background: Daucus gracilis Steinh belongs to the Apiaceae family. The flowers of this plant have been used by the population of western Algeria for the treatment of mouth ulcers. However, very few studies exist concerning the biological properties of essential oil of Daucus gracilis Steinh flowers. Objectives: The purpose of this work was to study the chemical composition of the essential oil of Daucus gracilis flowers and to evaluate their antimicrobial, insecticidal and anti-inflammatory properties. Methods: The distilled essential oil was analyzed by GC and GC-MS. The antimicrobial activity of the essential oil was evaluated using two methods i) diffusion method, and ii) micro dilution technique. The insecticidal activity of essential oil was evaluated against adults of Tribolium confusum by fumigant test. The in vitro assessment of the anti-inflammatory property of essential oil was assessed by the protein denaturation method. Results: Daucus gracilis flowers essential oil mainly represented oxygenated monoterpenes such as geranyl acetate (18.3%), lavandulyl acetate (15.2%), lavandulyl isobutyrate (13.6%) and citronellyl isobutyrate (6.8%). According to the results of antimicrobial activity, the essential oil of flowers presented prominent inhibitory action against Aspergillus flavus (0.06 μg/mL), followed by Staphylococcus aureus, Escherichia faecalis, Bacillus cereus and Candida albicans with MIC values of 0.125 μg/mL. The Daucus gracilis essential oil flowers proved to be very biocidal toward adults of Tribolium confusum; mortality of 100% of the population was noted with a dose of 2 μl/L air after 24 hours of exposure. Furthermore, the oil has shown a very good inhibition of protein denaturation comparable to Diclofenac at a concentration of 30 μL/mL. Conclusion: Daucus gracilis essential oil can be used as a pharmacological tools for inflammatory, antimicrobial and insecticidal properties.

Background: Microsomal prostaglandin E synthase-1 (mPGES-1) catalyzes the terminal step of prostaglandin E2 (PGE2) production, which plays an important role in the regulation of febrile response. In our previous work, ligand-based pharmacophore models, built with mPGES-1 inhibitors, were employed to identify a novel series of compounds that reduce the febrile response in rats. Objectives: The study aimed to evaluate the mechanism of action of the most active compound (1). Methods: For in vivo assays, rats were pretreated with the antipyretic compounds 1-8, 30 min before LPS injection. For in vitro assays, RAW 264.7 macrophage cells were incubated with the antipyretic compounds 1-8 for 1 hour before LPS stimulus. After 16 h, quantitative real-time PCR was carried out. Additionally, the PGE2 concentration in the hypothalamus was quantified by ELISA and the inhibitory effect of N-cyclopentyl-N'-[3-(3-cyclopropyl-1H-1,2,4-triazol- 5-yl)phenyl]ethanediamide (1) over human COX-2 enzymatic activity was determined with a COX Colorimetric Inhibitor Screening Assay Kit. Results: Compound 1 and CAY10526 showed comparable efficacy to reduce the febrile response when injected i.v. (compound 1: 63.10%, CAY10526: 70.20%). Moreover, compound 1 significantly reduced the mPGES-1 mRNA levels, in RAW264.7 cells, under inflammatory conditions. A chemically-similar compound (8-) also significantly reduced the mRNA levels of the gene target. On the other hand, compounds 6 and 7, which are also somewhat similar to compound 1, did not significantly impact mPGES-1 mRNA levels. Conclusions: PGE2 concentration reduction in the hypothalamus, due to compound 1 central injection, is related to decreased mPGES-1 mRNA levels but not to COX-2 inhibition (IC50> 50 μM). Therefore, compound 1 is a promising lead for innovative antipyretic drug development.

Background: Hydrocephalus is a complex neurologic disorder that has a widespread impact on the central nervous system and a multifactor disease which affects the CSF dynamics and causes severe neurological impairments in children. The pathophysiology of hydrocephalus is not fully understood. However, increasing evidence suggests that oxidative stress may be an important factor in the pathogenesis of hydrocephalus. Objective: The purpose of this study is to investigate the relationship of the KEAP-1/NRF-2/HO-1 pathway, one of the main regulators of the antioxidant system in the hydrocephalus pathology, on oxidative stress and tau protein level. Methods: The study included 32 patients with hydrocephalus and 32 healthy controls. KEAP-1, NRF-2, HO-1, TAU, and MPO levels are measured using ELISA method TAS, TOS, and Total THIOL colorimetric method. Results: KEAP-1, TAS, and Total THIOL levels were found significantly lowerer in the hydrocephalus group than in the control group. Nevertheless, it was identified that in the hydrocephalus group that the NRF-2, HO-1, TAU, MPO, TOS, and OSI levels were significantly elevated. Conclusion: In conclusion, although the KEAP-1/NRF-2/HO-1 pathway is activated in patients with hydrocephalus, it is identified that the antioxidant defense system is insufficient and ultimately leads to elevated oxidative stress. The elevation in the tau level may be an indicator of oxidative stress induced neurodegenerative damage.

Aim: To test the effectiveness of marketed polyherbal formulations on lipopolysaccharide-induced inflammatory conditions in macrophages. Background: Usage of herbal compounds among patients suffering from arthritis and cancer is increasing every year. Many anti-inflammatory herbal products available in the market should be screened thoroughly for their possible mechanism of action. Objective: Joint Pain Spl (JPS) is a polyherbal dietary food supplement composed of 13 herbal plants, and Rumalaya Forte (RF) is a polyherbal formulation comprising of 6 herbal plants. These were tested for their cytotoxicity, as well as antioxidant and anti-inflammatory activities in LPS treated IC-21 peritoneal macrophages. Methods: Commercially available JPS and RF powder was used to prepare the extract. The aqueous and methanol extracts were quantified for the presence of phenolic and flavonoid compounds and confirmed with HPLC. In vitro DPPH free scavenging activity was performed. Cytotoxicity was tested by MTT assay. Anti-inflammatory activity was tested using lipopolysaccharide-stimulated IC-21 peritoneal macrophage cells. Results: The phytochemical screening showed the presence of phenolic and flavonoid compounds in JPS and RF. The aqueous and methanol extracts of JPS and RF possesses significant DPPH free radical scavenging activity. MTT assay revealed that 90.64% (aqueous extract) and 92.21% (methanol extract) of exposed macrophages are viable even after 24h exposure of maximal tested concentrations of herbal formulations. Pre-treatment of JPS and RF on LPS induced IC-21 macrophages showed a reduction in nitric oxide production (maximal 79.95%) and a high level of superoxide anion scavenging activity (maximal 82.5%) over control. Conclusion: The two tested polyherbal formulations, such as JPS and RF possess anti-inflammatory activity by modulating free radical generation in IC-21 macrophages. Thus the presence of the phenolic and flavonoid compounds may contribute to the antioxidant activity.

Background & Aims: Pruritus associated with liver diseases confines daily activities and causes sleep deprivation in patients with chronic liver diseases. Autotoxin enzyme (ATX) was found to be higher in sera of patients with intrahepatic cholestasis and it was found to be associated with the intensity of itching. The aim of this study was to assess the correlation between the autotaxin enzyme and pruritus in Egyptian patients suffering from chronic liver disease (CLD). Methods: This cross-sectional study was carried on a total number of 80 patients with chronic liver disease divided into four groups: Group A and B included cirrhotic patients suffering from pruritis with and without cholestasis, while group C and D included patients without pruritis with or without cholestasis and group E included 17 healthy controls. They were subjected to measurement of serum autotoxin concentration by ELISA in addition to routine investigations including liver function tests: Total and direct bilirubin, ALT, AST, Alkaline phosphatase, Gama- glutamyl transferase, and serum albumin. Results: There was a significant increase in autotaxin in the four groups included chronic liver disease patients (P-value <0.001*) compared to control group (group E). Autotoxin level was the only marker that had a significant increase in pruritus groups (groups A & B) compared to non-pruritus groups (groups C & D) with cut off value ≥ 32. Conclusion: Serum autotaxin level was elevated in patients with chronic liver diseases with pruritus. Autotaxin enzyme may play a key role in the induction of hepatogenic pruritus. So, autotaxin enzyme inhibitors and lysophosphatidic acid (LPA) receptor blockers could be a future line of treatment of hepatogenic pruritus.

Aims: The present investigation was aimed at exploring the phytoconstituents using Gas Chromatography Mass Spectroscopy and to evaluate antioxidant and anti-inflammatory properties of the leaf extracts. Materials and Methods: The extracts were obtained sequentially with petroleum ether, ethyl acetate and water using Soxhlet apparatus. The anti-inflammatory property of the identified compounds using GC- MS spectroscopy was evaluated in silico. The antioxidant activity was performed by DPPH and H2O2 method whereas anti-inflammatory study was carried out by HRBC membrane stabilization method. Terpenoids were found to be a major constituents in petroleum ether extract while, phenols and flavonoids were predominantly found in ethyl acetate extract. Results and Discussion: The GC-MS analysis of the extract revealed six major molecules including Squalene, 19β, 28-epoxyleanan-3-ol and 2-tu-Butyl-5-chloromethyl-3-methyl-4-oxoimidazolidine- 1-carboxylic acid. The ethyl acetate extract showed a significant antioxidant activity (P<0.01) in both DPPH method (70.87%) and H2O2 method (73.58%) at 200 μg mL^-1. Increased membrane stabilization of petroleum ether extract was observed in the in vitro anti-inflammatory activity study. A strong relationship between the terpenoid content and anti-inflammatory activity was obtained from the correlation (0.971) and docking study. Conclusion: These results justify T. involucrata to be a rich source of terpenoids with potent anti- inflammatory property.