Phytochemicals and Their Usefulness in the Maintenance of Health.

Inflammation is the immune system's first biological response to infection, injury, or irritation. Evidence suggests that the anti-inflammatory effect is mediated by the regulation of various inflammatory cytokines, such as nitric oxide, interleukins, tumor necrosis factor alpha-α, interferon gamma-γ, as well as the non-cytokine mediator, prostaglandin E2. Currently, the mechanism of action and clinical usefulness of phytochemicals is known; their action on the activity of cytokines, free radicals, and oxidative stress. The latter are of great relevance in the development of diseases, such that the evidence collected demonstrates the beneficial effects of phytochemicals in maintaining health. Epidemiological evidence indicates that regular consumption of fruits and vegetables is related to a low risk of developing cancer and other chronic diseases.

Chiranthodendron pentadactylon Larreat (Sterculiaceae), a Potential Nephroprotector against Oxidative Damage Provoked by STZ-Induced Hyperglycemia in Rats.

BACKGROUND: Chiranthodendron pentadactylon, known in Mexico as the "tree of the little hands", flower's infusion is used to treat kidney failure associated with diseases such as diabetes. The aim of this work is to evaluate the antioxidant effect of the methanolic extract of its flowers on oxidative damage in kidneys caused by streptozotocin in rats. METHODS: The extract phytochemical profile was performed with HPLC. Antioxidant potential in vitro was determined with DPPH and total phenolic tests; antioxidant evaluation in vivo was performed in diabetic rats administered daily via the intragastric route (100 and 200 mg/kg) for 6 weeks; serum glucose/creatinine, food/water consumption, and urinary volume were measured. Relative weight, protein/DNA ratios and oxidative stress were measured in renal tissue. RESULTS: The extract showed 20.53% of total phenolic content and IC50 of 18.05 µg/mL in DPPH, and this was associated with ferulic acid, phloretin and α-amyrin. Both doses showed a moderate decrease in the protein/DNA ratio in renal tissue, and the same behavior was observed for total urinary protein loss and serum creatinine, while the best antioxidant effect was exerted by a lower dose, which increased catalase activity and decreased lipid peroxidation in the kidneys. CONCLUSIONS: Results demonstrated that C. pentadactylon methanolic flower's extract improves renal function through antioxidant mechanisms during experimental diabetes.

Polyamines modulate mouse sperm motility.

Polyamines are polycationic molecules which contains two or more amino groups (-NH3+) highly charged at physiological pH, and among them we found spermine, spermidine, putrescine, and cadaverine. They interact with proteins, nucleic acids, modulate Ca2+, K+, and Na+ channels, and protect sperm from oxidative stress. In this work, we evaluate the effect of spermine, spermidine, and putrescine on the total, progressive and kinematic parameters of motility, capacitation, acrosome reaction, also in presence and absence of the dbcAMP, an analogue of the cAMP, and the IBMX, a phosphodiesterase inhibitor. In addition, we evaluated the intracellular concentrations of cAMP [cAMP]i, and performed an in silico analysis between polyamines and the sAC from mouse to predict the possible interaction among them. Our results showed that all polyamines decrease drastically the total, progressive and the kinetic parameters of sperm motility, decrease the capacitation, and only spermidine and putrescine impeded the acquisition of acrosome reaction. Moreover, the effect of polyamines was attenuated but not countered by the addition of db-cAMP and IBMX, suggesting a possible inhibition of the sAC. Also, the presence of polyamines induced a decrease of the [cAMP]i, and the in silico analysis predicted a strong interaction among polyamines and the sAC. Overall, the evidence suggests that probably the polyamines interact and inhibit the activity of the sAC.

C-Phycocyanin: A Phycobiliprotein from Spirulina with Metabolic Syndrome and Oxidative Stress Effects.

Spirulina maxima is a cyanobacterium considered a "superfood" due to its metabolites and nutrient content. These include a complex mixture of minerals, vitamins, fatty acids, proteins, and accessory pigments. In recent years, it has positioned itself as a promising source of bioactive molecules for the treatment of several diseases, including metabolic syndrome, coronary diseases, cancer, and the improvement of health modulating oxidative stress. C-Phycocyanin (C-PC) is a photosynthetic pigment from green-blue cyanobacterium and the most abundant phycobiliprotein in the Spirulina genus with various pharmacological properties attributed due to its antioxidant capacity but has no specific cellular target. This has made it a molecule of great interest in biomedical research. This review focuses on the pharmacological effects and the benefits on metabolic syndrome and oxidative stress of C-PC.

Developmental Toxicity Study of DL-4-Hydroxy-4-Phenylhexanamide (DL-HEPB) in Rats.

Antiepileptic drugs affect embryonic development when administered during pregnancy, generating severe alterations, such as as cleft lip, spina bifida, heart abnormalities, or neuronal alterations. The compound DL-4-hydroxy-4-phenylhexanamide (DL-HEPB), a phenyl alcohol amide structurally different from known anticonvulsants, has shown good anticonvulsant effects in previous studies. However, its effects on intrauterine development are unknown. So, the purpose of this study was to determine the potential of DL-HEPB to produce alterations in conceptus. Pregnant Wistar rats were orally exposed to 0, 50, 100, and 200 mg/kg of DL-HEPB during organogenesis, and their food consumption and weight gain were measured. On gestation day 21, pregnant females were euthanized to analyze the fetuses for external, visceral, and skeletal malformations. A significant decrease in food consumption and body weight was observed in mothers, without any other manifestation of toxicity. In fetuses, no external malformations, visceral, or skeletal abnormalities, were observed under the dose of 100 mg/kg, while the dose of 200 mg/kg caused malformations in low frequency in brain and kidneys. In view of the results obtained, DL-HEPB could be a good starting point for the design of new highly effective anticonvulsant agents, with much lower developmental toxicity than that shown by commercial anticonvulsants.

Spirulina (Arthrospira maxima) mitigates the toxicity induced by a mixture of metal and NSAID in Xenopus laevis.

Cadmium (Cd) is often detected in the environment due to its wide use in industry; also, NSAIDs are one of the most consumed pharmaceuticals, particularly diclofenac (DCF). Several studies have reported the presence of both contaminants in water bodies at concentrations ranging from ng L-1 to µg L-1; in addition, they have shown that they can induce oxidative stress in aquatic species and disturb signal transduction, cell proliferation, and intercellular communication, which could lead to teratogenesis. Spirulina has been consumed as a dietary supplement; its antioxidant, anti-inflammatory, neuroprotective, and nutritional properties are well documented. This work aimed to evaluate if Spirulina reduces the damage induced by Cd and DCF mixture in Xenopus laevis at early life stages. FETAX assay was carried out: 20 fertilized oocytes were exposed to seven different treatments on triplicate, control, Cd (24.5 µg L-1), DCF (149 µg L-1), Cd + DCF, Cd+DCF+Spirulina (2 mg L-1), Cd+DCF+Spirulina (4 mg L-1), Cd+DCF+Spirulina (10 mg L-1), malformations, mortality, and growth were evaluated after 96 h, also lipid peroxidation, superoxide dismutase and catalase activity were determined after 192 h. Cd increased DCF mortality, Cd and DCF mixture increased the incidence of malformations as well as oxidative damage; on the other hand, the results obtained show that Spirulina can be used to reduce the damage caused by the mixture of Cd and DCF since it promotes growth, reduce mortality, malformations, and oxidative stress in X. laevis.

Protective Effect of the Phycobiliproteins from Arthrospira maxima on Indomethacin-Induced Gastric Ulcer in a Rat Model.

Gastric ulcers (GU) constitute a disease with a global prevalence ≈ 8.09 million. Of their causes, non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (IND) rank as the second most frequent etiologic agent. The pathogenic process of gastric lesions is given by the overproduction of oxidative stress, promotion of inflammatory processes, and inhibition of prostaglandin synthesis. Spirulina Arthrospira maxima (SP) is a cyanobacterium with a wide variety of substances with high nutritional and health values such as phycobiliproteins (PBPs) that have outstanding antioxidant activity, anti-inflammatories effects, and accelerate the wound healing process. This study aimed to determine the protective effect of PBPs in GU induced by IND 40 mg/kg. Our results show that the PBPs protected against IND-induced damage with a dose-dependent effect. At a dose of 400 mg/kg, a marked decrease in the number of lesions is observed, as well as the recovery of the main markers of oxidative stress damage (MDA) and antioxidant species (SOD, CAT, GPx) at close to baseline levels. The evidence derived from the present investigation suggests that the antioxidant effect of PBPs, together with their reported anti-inflammatory effects to accelerate the wound healing process, is the most reliable cause of their antiulcerogenic activity in this GU model.

Effects of Spirulina maxima on a Model of Sexual Dysfunction in Streptozotocin-Induced Diabetic Male Rats.

Arthrospira (Spirulina) maxima (SM) is a cyanobacterium that has a long history of being used as human food. In recent years, several investigations have shown its beneficial biological effects, among which its antioxidant capacity has been highlighted. The purpose of this study was to evaluate the effects of SM on body weight, glycemia, sexual behavior, sperm quality, testosterone levels, sex organ weights, and the activity of antioxidant enzymes in diabetic male rats (a disease characterized by an increase in reactive oxygen species). The experiment consisted of six groups of sexually expert adult males (n = 6): (1) control (vehicle); (2) streptozotocin (STZ)-65 mg/kg; (3) SM-400 mg/kg; (4) STZ + SM-100 mg/kg; (5) STZ + SM-200 mg/kg; and (6) STZ + SM-400 mg/kg. Sexual behavior tests were performed during the first 3 h of the dark period under dim red illumination. Our results showed that SM significantly improved sexual behavior and sperm quality vs. diabetic animals. Likewise, while the enzymatic activities of SOD and GPx increased, TBARS lipoperoxidation decreased and testosterone levels increased. In view of the findings, it is suggested that SM may potentially be used as a nutraceutical for the treatment of diabetic male sexual dysfunction due to its antioxidant property.

Participation of signaling proteins in sperm hyperactivation.

Sperm hyperactivation is described as a fast whip movement of the flagellum, an irregular trajectory, and an asymmetrically flagellum bend. This motility pattern is achieved during the passage of the sperm along the female genital tract. It helps the spermatozoa to cross through different viscous ambient fluids to finally reach the oocyte. Important signaling proteins are located in the sperm head and flagellum, and they all play an important role in the cascade that controls the sperm hyperactivation. The presence of HCO3- modulates the activity of the soluble adenylyl cyclase (sAC), leading to the production of cAMP. In turn, cAMP modulates the sperm-specific Na+/H+ exchanger (sNHE) and the t-complex protein 11 (TCP11) which play an essential role on the signaling pathway (cAMP/PKA and tyrosine phosphorylation) and sperm hypermotility. sNHE, cystic fibrosis transmembrane conductance regulator (CFTR), and voltage-gated proton channel (Hv) mainly contribute to the regulation of the intracellular pH (pHi) during capacitation. HCO3- entrance and the removal of H+ from the cytoplasm induces the alkalization of pHi, and this change will contribute to the activation of the cation channel of sperm (CatSper). Recently, it was described the participation on sperm motility and the regulation of calcium channels of an autophagy-related protein, the microtubule-associated protein light chain 3 (LC3). This review gathers important literature about the essential roles of sAC, sNHE, CFTR, Hv, and CatSper in the acquisition of sperm hyperactivation, and provides an integrated overview of recently described roles of TCP11 and LC3 on the sperm signaling pathway. Additionally, we provide insight into the infertility induced by the dysfunction of these critical proteins.

A Complete Review of Mexican Plants with Teratogenic Effects.

In Mexico, the use of medicinal plants is the first alternative to treat the diseases of the most economically vulnerable population. Therefore, this review offers a list of Mexican plants (native and introduced) with teratogenic effects and describes their main alterations, teratogenic compounds, and the models and doses used. Our results identified 63 species with teratogenic effects (19 native) and the main alterations that were found in the nervous system and axial skeleton, induced by compounds such as alkaloids, terpenes, and flavonoids. Additionally, a group of hallucinogenic plants rich in alkaloids employed by indigenous groups without teratogenic studies were identified. Our conclusion shows that several of the identified species are employed in Mexican traditional medicine and that the teratogenic species most distributed in Mexico are Astragalus mollissimus, Astragalus lentiginosus, and Lupinus formosus. Considering the total number of plants in Mexico (≈29,000 total vascular plants), to date, existing research in the area shows that Mexican plants with teratogenic effects represent ≈0.22% of the total species of these in the country. This indicates a clear need to intensify the evaluation of the teratogenic effect of Mexican plants.

Antifungal Activity of Fibrate-Based Compounds and Substituted Pyrroles That Inhibit the Enzyme 3-Hydroxy-methyl-glutaryl-CoA Reductase of Candida glabrata (CgHMGR), Thus Decreasing Yeast Viability and Ergosterol Synthesis.

Due to the emergence of multidrug-resistant strains of yeasts belonging to the Candida genus, there is an urgent need to discover antifungal agents directed at alternative molecular targets. The aim of the current study was to evaluate the capacity of three different series of synthetic compounds to inhibit the Candida glabrata enzyme denominated 3-hydroxy-methyl-glutaryl-CoA reductase and thus affect ergosterol synthesis and yeast viability. Compounds 1c (α-asarone-related) and 5b (with a pyrrolic core) were selected as the best antifungal candidates among over 20 synthetic compounds studied. Both inhibited the growth of fluconazole-resistant and fluconazole-susceptible C. glabrata strains. A yeast growth rescue experiment based on the addition of exogenous ergosterol showed that the compounds act by inhibiting the mevalonate synthesis pathway. A greater recovery of yeast growth occurred for the C. glabrata 43 fluconazole-resistant (versus fluconazole-susceptible) strain and after treatment with 1c (versus 5b). Given that the compounds decreased the concentration of ergosterol in the yeast strains, they probably target ergosterol synthesis. According to the docking analysis, the inhibitory effect of 1c and 5b could possibly be mediated by their interaction with the amino acid residues of the catalytic site of the enzyme. Since 1c displayed higher binding energy than α-asarone and 5b, it is the best candidate for further research, which should include structural modifications to increase its specificity and potency. The derivatives could then be examined with in vivo animal models using a therapeutic dose. IMPORTANCE Within the context of the COVID-19 pandemic, there is currently an epidemiological alert in health care services due to outbreaks of Candida auris, Candida glabrata, and other fungal species multiresistant to conventional antifungals. Therefore, it is important to propose alternative molecular targets, as well as new antifungals. The three series of synthetic compounds herein designed and synthesized are inhibitors of ergosterol synthesis in yeasts. Of the more than 20 compounds studied, two were selected as the best antifungal candidates. These compounds were able to inhibit the growth and synthesis of ergosterol in C. glabrata strains, whether susceptible or resistant to fluconazole. The rational design of antifungal compounds derived from clinical drugs (statins, fibrates, etc.) has many advantages. Future studies are needed to modify the structure of the two present test compounds to obtain safer and less toxic antifungals. Moreover, it is important to carry out a more in-depth mechanistic approach.

Phycobiliproteins extract from Spirulina protects against single-dose cadmium-induced reproductive toxicity in male mice.

Cadmium (Cd) is known for its many toxic effects on male population such as hypogonadism and fertility difficulties, which are oftenly associated with oxidative stress. As beneficial food, Spirulina(Sp) has been proved efficient against the heavy metal toxicity. This capacity can be associated with its phycobiliproteins (PBP). In this study, the capability of PBP and Sp to treat Cd-induced oxidative damage on the testes and spermatozoa was considered. CD-1 strain mice were orally treated with either Sp or PBP for 10 days prior to single-dose Cd challenge. Sperm quality determinations and testicle histology analysis were performed. Testosterone on serum was measured using enzyme-linked immunosorbent assay (ELISA). Oxidative damage was determined. Antioxidant enzyme activity was analyzed by measuring the activity of super oxide dismutase (SOD), catalase (Cat), and glutathione peroxidase (GpX). The motility and viability of sperm decrease with Cd and improve with PBP and Sp, as the acrosomal reaction (AR) is diminished by PBPs. Testosterone levels decrease due to Cd, and only Sp maintains elevated levels. Cd increases the production of malondialdehyde in the spermatozoa, but not in testes; this production of malondialdehyde in the spermatozoa decreases in the presence of PBP. ROS only decreases with Cd, FBP, and Sp at high concentrations. Advanced oxidative protein products (AOPP) decrease with Cd and PBPs. Cat and GpX increase their activity with Cd and are altered by FBP. Cd produces vascular alterations testes. Within the seminiferous tubule, it produces areas of necrosis and apoptosis, which improve with PBPs and Sp. PBPs have a strong antioxidant activity as they show protective properties against Cd oxidative-induced toxicity on testes and sperm.

Development, Characterization, Optimization, and In Vivo Evaluation of Methacrylic Acid-Ethyl Acrylate Copolymer Nanoparticles Loaded with Glibenclamide in Diabetic Rats for Oral Administration.

The methacrylic acid-ethyl acrylate copolymer nanoparticles were prepared using the solvent displacement method. The independent variables were the drug/polymer ratio, surfactant concentration, Polioxyl 40 hydrogenated castor oil, the added water volume, time, and stirring speed, while size, PDI, zeta potential, and encapsulation efficiency were the response variables analyzed. A design of screening experiments was carried out to subsequently perform the optimization of the nanoparticle preparation process. The optimal formulation was characterized through the dependent variables size, PDI, zeta potential, encapsulation efficiency and drug release profiles. In vivo tests were performed in Wistar rats previously induced with diabetes by administration of streptozotocin. Once hyperglycemia was determined in rats, a suspension of nanoparticles loaded with glibenclamide was administered to them while the other group was administered with tablets of glibenclamide. The optimal nanoparticle formulation obtained a size of 18.98 +/- 9.14 nm with a PDI of 0.37085 +/- 0.014 and a zeta potential of -13.7125 +/- 1.82 mV; the encapsulation efficiency was of 44.5%. The in vivo model demonstrated a significant effect (p < 0.05) between the group administered with nanoparticles loaded with glibenclamide and the group administered with tablets compared to the group of untreated individuals.

Oxidative Stress, Mitochondrial Function and Adaptation to Exercise: New Perspectives in Nutrition.

Cells have the ability to adapt to stressful environments as a part of their evolution. Physical exercise induces an increase of a demand for energy that must be met by mitochondria as the main (ATP) provider. However, this process leads to the increase of free radicals and the so-called reactive oxygen species (ROS), which are necessary for the maintenance of cell signaling and homeostasis. In addition, mitochondrial biogenesis is influenced by exercise in continuous crosstalk between the mitochondria and the nuclear genome. Excessive workloads may induce severe mitochondrial stress, resulting in oxidative damage. In this regard, the objective of this work was to provide a general overview of the molecular mechanisms involved in mitochondrial adaptation during exercise and to understand if some nutrients such as antioxidants may be implicated in blunt adaptation and/or an impact on the performance of exercise by different means.

Phycobiliproteins Ameliorate Gonadal Toxicity in Male Mice Treated with Cyclophosphamide.

Cyclophosphamide (CP)-which is used to treat autoimmune diseases and cancer-is related to gonadotoxicity attributed to oxidative stress. As phycobiliproteins (PBPs) are strong antioxidants that are unexplored as protective agents against male gonadotoxicity, our work aimed to investigate the effects of PBP crude extract on testicular damage and sperm parameter alterations caused by CP in mice. Three doses of PBP (50, 100, and 200 mg/kg) were tested in the experimental groups (n = 8 per group), administered concomitantly with 100 mg/kg CP. After 42 days receiving PBP daily and CP weekly, body and relative testicular weights, serum testosterone levels, testicular lipoperoxidation and antioxidant enzyme activity levels, and testicular histology and sperm parameter alterations were assessed. The results showed that PBP crude extract at 200 mg/kg prevented testosterone serum reduction, body weight loss, lipoperoxidation and enzyme activity increments, and sperm parameter alterations and partially ameliorated relative testicular weight reductions and histological damage in CP-treated mice. In conclusion, we showed that PBP crude extract (200 mg/kg) mitigated oxidative damage in the testes and ameliorated alterations in sperm parameters in mice treated with CP (100 mg/kg); therefore, PBP extract could be considered as a potential protective agent against CP toxicity.

Protective effects of Spirulina (Arthrospira maxima) against toxicity induced by cadmium in Xenopus laevis.

Spirulina (Arthrospira maxima) has been recognized as a superfood and nutraceutical by its high nutritional value and the benefits of its consumption; it is an important source of lipids, proteins, vitamins, minerals, and antioxidants. It is known that spirulina has positive effects on the toxicity induced by pharmaceuticals and metals. Heavy metals such as cadmium, frequently used in industrial activities, are continuously detected in water bodies and can generate adverse effects on aquatic organisms even at low concentrations. This study aimed to evaluate the protective effect of spirulina (Arthrospira maxima) against the toxic effects induced by cadmium in the early life stages of Xenopus laevis. Twenty Xenopus laevis embryos were exposed to five different treatments on triplicate, control, cadmium (CdCl2 24.5 µg L-1) and three spirulina mixtures Cd + S 1 (24.5 µg L-1 CdCl2 + 2 mg L-1 spirulina), Cd + S 2 (24.5 µg L-1 CdCl2 + 2 mg L-1 spirulina), Cd + S 3 (24.5 µg L-1 CdCl2 + 10 mg L-1 spirulina); after 96 h of exposure: Malformations, mortality and length were evaluated; also, after 192 h, lipid peroxidation (LPX), superoxide dismutase (SOD) and catalase (CAT) were determined. All spirulina treatments decreased mortality from 34 to 50% and reduced malformations on incidence from 36 to 68%. Treatment Cd + S 3 decreased growth inhibition significantly. Spirulina treatment Cd + S 2 decreased lipidic peroxidation and antioxidant activity; these results suggest that spirulina (Arthrospira maxima) can decrease the mortality, frequency of malformations, the severity of malformations, growth inhibition, and oxidative damage induced by cadmium in Xenopus laevis embryos.

Anticonvulsive profile of two GABAB receptor antagonists on acute seizure mice models.

INTRODUCTION: DL-3-hydroxy-3-phenylpentanamide (HEPP) and DL-3-hydroxy-3-(4'chlorophenyl)-pentanamide (Cl-HEPP) are phenyl-alcohol-amides that are metabotropic GABAB receptor (MGBR) antagonists and protective against absence seizures. This study aims to further characterize the anticonvulsant profile of these drugs. METHODS: HEPP and Cl-HEPP were evaluated in various standardized acute seizure and toxic tests in female Swiss-OF1 mice. RESULTS: Toxicities of HEPP and Cl-HEPP were limited; doses up to 30 mg/kg did not result in hypothermia, reduced spontaneous locomotor activity, or failure of the rotarod test, with doses >15 mg/kg potentiating pentobarbital-induced sleep. In maximal electroshock-induced seizures, 20 mg/kg Cl-HEPP protected 100 % of mice; lower doses shortened post-ictal recovery. Seizure protection occurred against subcutaneous pentylenetetrazole and picrotoxin, being limited against N-methyl-d-aspartate. In bicuculline test, clonic or fatal tonic seizures were decreased, onset delayed, and recovery improved; ED50 values (dose protecting 50 % of the animals) were 37.5 and 25 mg/kg for HEPP and Cl-HEPP, respectively. In magnesium deficiency-dependent audiogenic seizures (MDDAS), ED50 values were 3 and 8 mg/kg for Cl-HEPP and HEPP, respectively. The components of MDDAS (latency, wild running, seizure, and recovery phases) in unprotected animals were only minimally affected by near ED50 doses of Cl-HEPP and HEPP. DISCUSSION: HEPP and, to a greater extent, Cl-HEPP provide anti-seizure protections in several acute seizure tests in mice at nontoxic doses. These results are consistent with the action of these drugs on diverse molecular targets directly resulting from their MGBR antagonistic properties. However, other mechanisms might occur possibly for the protection given in the MES test. Finally, a similarity in the modulation of MDDAS components between the two phenyl alcohol amides and ethosuximide could also be based on the MGBR antagonistic properties of the former, given the recently re-evaluated therapeutic relevant targets of the latter.

Anti-epileptic activity, toxicity and teratogenicity in CD1 mice of a novel valproic acid arylamide derivative, N-(2-hydroxyphenyl)-2-propylpentanamide.

N-(2-hydroxyphenyl)-2-propylpentamide (HO-AAVPA) is a novel arylamide derivative of valproic acid (VPA) designed in silico, with better antioxidant and antiproliferative effect on cancer cell lines than VPA. This study was aimed to evaluate the anticonvulsant activity, the toxicity and teratogenicity produced in HO-AAVPA-treated CD1 mice using VPA as positive control. With the maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizure models, HO-AAVPA reduced the time of hind limb extension, stupor and recovery, the number of clonic and tonic seizures and the mortality rate in a dose-dependent manner, obtaining an ED50 of 370 and 348 mg/kg for MES and PTZ, respectively. On the rotarod test, mice administered with 600 mg/kg HO-AAVPA manifested reduced locomotor activity (2.78%); while HO-AAVPA at 300 mg/kg and VPA at 500 mg/kg gave a similar outcome (∼60%). The LD50 of 936.80 mg/kg herein found for HO-AAVPA reflects moderate toxicity. Concerning teratogenicity, the administration of HO-AAVPA to pregnant females at 300 and 600 mg/kg on gestation day (GD) 8.5 generated less visceral and skeletal alterations in the fetuses, as well as, minor rate of modifications in the expression pattern of the neuronal marker Tuj1 and endothelial marker PECAM1 in embryos, that those induced by VPA administration. Altered embryonic development occurred with less frequency and severity with HO-AAVPA at 600 mg/kg than VPA at 500 mg/kg. In conclusion, the protective effect against convulsions provided by HO-AAVPA was comparable to that of VPA in the MES and PZT seizure models, showed lower toxicity and less damage to embryonic and fetal development.

Synthesis and highly potent anti-inflammatory activity of licofelone- and ketorolac-based 1-arylpyrrolizin-3-ones.

Since NSAIDs are commonly used anti-inflammatory agents that produce adverse effects, there have been ongoing efforts to develop more effective and less toxic compounds. Based on the structure of the anti-inflammatory pyrrolizines licofelone and ketorolac, a series of 1-arylpyrrolizin-3-ones was synthesized. Also prepared was a series of substituted pyrroles, mimicking similar known anti-inflammatory agents. The anti-inflammatory activity of the test compounds was determined with a phorbol ester (TPA)-induced murine ear edema protocol. For the most active derivatives, 19b-c/20b-c, the anti-inflammatory effect was the same as that of the reference compound (indomethacin) and was dose-dependent. These compounds have an aryl ring at the C-1 position and a methoxycarbonyl group at the C-2 position of the pyrrolizine framework, which represent plausible pharmacophore groups with anti-inflammatory activity. The anti-inflammatory activity of 1-substituted analogs containing a five- or six-membered heterocycles was lower but still good, while that of the pyrroles was only moderate. Although the docking studies suggests that the effect of analogs 19a-c/20a-c is associated with the inhibition of cyclooxygenase-2, experimental assays did not corroborate this idea. Indeed, a significant inhibition of NO was found experimentally as a plausible mechanism of action.