Evaluation of antioxidant potencial of novel CaAl and NiAl layered double hydroxides loaded with olanzapine.

Olanzapine (OLZ), is used in the treatment of bipolar disorder and schizophrenia, diseases that present oxidative stress in their physiopathology. It has low aqueous solubility, which may lead to low oral bioavailability. The search of new drug delivery systems (DDSs) that may increase dissolution rate of OLZ, associated with the investigation of the antioxidant potential of the loaded-systems become of major importance to understand improvement in bipolar disorder and schizophrenia therapy. Thus, this study aimed to evaluate the in vitro antioxidant potential of two different Layered Double Hydroxides (LDH) loaded with 5% of OLZ (CaAl and NiAl), by radical scavenging activity (2,2-Diphenyl-1-picrylhydrazyl and nitric oxid); radical cation scavenging activity (2,2'-azino-bis3-ethylbenzthiazoline-6-sulfonic acid ABTS) and evaluation of inhibition capacity of lipid peroxidation by thiobarbituric acid (TBARS). The results showed that both obtained LDH systems presented in vitro antioxidant capacity when associated with OLZ in all methods performed, and this activity is more pronounced with the systems containing OLZ compared to pure drug. The systems with CaAl was shown to have increased antioxidant potential, compared to NiAl, increasing the antioxidant activity up to 40,83%, 15,84% and 16,73%, as showed by the DPPH, nitric oxide and TBARS tests, respectively. The results revealed that the use of LDHs as a functional excipient may be promising in the pharmaceutical industry for bipolar disorder and schizophrenia therapy.

Effects of isopentyl ferulate on oxidative stress biomarkers and a possible GABAergic anxiolytic-like trait in Swiss mice.

This study aimed to evaluate the anxiolytic-like effect and the possible neuronal mechanism of action of isopentyl ferulate (IF). For this purpose, we used the marble burying test in Swiss albino mice. The biomarkers involved in oxidative stress were measured in the hippocampus homogenate of the test animals. In addition, the toxicity and antioxidant capacities were tested in Artemia salina and rat erythrocytes, respectively. The results suggest that, an acute administration of the IF at doses of 25, 50, 75 and 150 mg/kg (intraperitoneal, i.p.) significantly (p < 0.05) reduced the marble burying behavior of the animals as compared to the vehicle group, which demonstrates a calming effect of this chemical. It was observed that, the pre-treatment with flumazenil (2.5 mg/kg, i.p.), an antagonist of the gamma-amino butyrinc acid (GABAA) receptor, significantly reversed the marble burying behavioral activity in the animals treated with the IF 150 mg/kg dose. Moreover, the reduction in nitrite content and lipid peroxidation levels, while an increased in the reduced glutathione (GSH), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) activities were also observed their hippocampus. Although, IF (2.36-14.16 mM) did not show toxicity in A. salina but exhibited a prominent antioxidant capacity in hydrogen peroxide-induced oxidative damage in rat erythrocytes. In conclusion, IF exhibited an anxiety-like effect in mice along with a potent antioxidant capacity, and we suppose it may have neuroprotective effects possibly via GABAergic transmission pathway.

Physio-pharmacological Investigations About the Anti-inflammatory and Antinociceptive Efficacy of (+)-Limonene Epoxide.

D-limonene epoxidation generates (+)-limonene epoxide, an understudied compound in the pharmacologically point of view. Herein, we investigated the anti-inflammatory and antinociceptive potentialities of (+)-limonene epoxide and suggested a mechanism of action. The anti-inflammatory potential was analyzed using agents to induce paw edema, permeability, and myeloperoxidase (MPO) activity. Pro-inflammatory cytokines and cell migration of peritoneal cells were also assessed. Antinociceptive effects were evaluated by writhing test induced by acetic acid, formalin, and hot plate assays and contribution of opioid pathways. Pretreated animals with (+)-limonene epoxide showed reduced carrageenan-induced paw edema in all doses (25, 50, and 75 mg/kg) (P < 0.05). At 75 mg/kg, it suppressed edema provoked by compound 48/80, histamine, prostaglandin E2, and serotonin and reduced permeability determined by Evans blue and MPO activity. It also reduced leukocytes, neutrophils, and IL-1ß levels in the peritoneal cavity in comparison with carrageenan group (P < 0.05). (+)-Limonene epoxide diminished abdominal contortions induced by acetic acid (78.9%) and paw licking times in both 1 (41.8%) and 2 (51.5%) phases and a pretreatment with naloxone (3 mg/kg) reverted the antinociceptive action in morphine- and (+)-limonene epoxide-treated groups (P < 0.05). Additionally, it enlarged response times to the thermal stimulus after 60 and 90 min. In conclusion, (+)-limonene epoxide inhibited release/activity of inflammatory mediators, vascular permeability, migration of neutrophils and displayed systemic and peripheral analgesic-dependent effects of the opioid system.

Antidepressant-like activity of liposomal formulation containing nimodipine treatment in the tail suspension test, forced swim test and MAOB activity in mice.

Previous studies have shown that intracellular calcium ion dysfunction may be an etiological factor in affective illness. Nimodipine (NMD) is a Ca(2+) channel blocker that has been extensively investigated for therapy of central nervous system (CNS) disorders. In this work, we have evaluated the antidepressant-like activity of nimodipine encapsulated into liposomes (NMD-Lipo) in mice through tail suspension and forced swim assays, as well as MAOB activity. During the tail suspension test, the administration of NMD-Lipo at 0.1, 1 and 10mg/kg was able to promote a reduction in the immobility time of animals greater than the positive control (imipramine). In the forced swim test, the immobility time of mice treated with NMD-Lipo was reduced. This reduction was significantly greater than that found in the animals treated with imipramine and paroxetine. This may suggest that NMD-Lipo provides more antidepressant-like activity than in positive controls. The groups that received a combination of liposomal NMD and antidepressant drugs showed lower immobility time than the groups, which were treated only with imipramine or paroxetine. The mice treated with the combination of NMD-Lipo and reserpine presented an increase in the time of immobility compared with animals treated only with NMD-Lipo. There was a significant decrease in MAOB activity in animals treated with NMD-Lipo compared with untreated animals. The results of the tail suspension test, forced swim test and MAOB activity suggested that the antidepressant activity of NMD-Lipo may be related to an increase in the cerebral monoamine concentrations.

Pre-clinical toxicology of garcinielliptone FC, a tautomeric pair of polyprenylated benzophenone, isolated from Platonia insignis Mart seeds.

BACKGROUND: Garcinielliptone FC (GFC) is a tautomeric pair of polyprenylated benzophenone, which has proven to have antiepileptic, cytotoxic and antioxidant activity. PURPOSE: The aim of this study was to investigate the biochemical, hematological and pathological effects of the acute toxicity study as well as to assess the locomotor activity and motor coordination in mice treated with GFC. METHODS: Swiss mice of both sexes weighing 25-30 g divided into three separate groups of five animals matched by weight and size. GFC was aseptically suspended in 0.05% Tween 80, dissolved in 0.9% saline (vehicle) and administered orally (p.o.) and intraperitoneally (i.p.) (500, 1000 and 2000 mg/kg). The acute toxicity study was performed in compliance with the Anvisa regulations. RESULTS: Behavioral manifestations of toxicity, such as state of consciousness, coordination, muscle tone, reflexes, the activity on the central nervous system (shake, seizures, Straub tail reaction and anesthesia) and the activity of the autonomic nervous system (lacrimation, ptosis, urination, piloerection, hypothermia, breathing and hyperemia) were not seen in any of the animals treated with doses of 500, 1000 and 2000 mg/kg. Additionally, no significant difference in body weight, food and water intake, excreta production or macroscopic changes in the organs of treated animals were detected in comparison with control group. GFC did not affect the locomotor activity and motor coordination of the animals. CONCLUSION: The acute toxicity study indicated that GFC treatment, at selected doses given orally and intraperitoneally, showed relatively low risk of toxicity in all test animals, suggesting that it is safe for further investigation.

In vitro antioxidant, antitumor and leishmanicidal activity of riparin A, an analog of the Amazon alkamides from Aniba riparia (Lauraceae) / Atividade antioxidante, antitumoral e leishmanicida in vitro da riparina A, um análogo das alcamidas amazônicas de Aniba riparia (Lauraceae)

Aniba riparia (Lauraceae) is an important medicinal plant found in the Amazon region and presents alkaloids of the type alkamide known as riparins. Riparin A is structurally represented as the fundamental core of all Amazon riparins. This work aimed to assess the in vitro antioxidant, antitumor and antileishmanial effects of riparin A. Riparin A presented weak antioxidant capacity by tecniques of DPPH• (EC50 of 296.2 μg mL-1) and ABTS•+ (EC50 of 450.1 μg mL-1), showed moderate activity against colon carcinoma (HCT-116: IC50 of 21.7 μg mL-1) and leishmanicidal activity on promastigotes of L. amazonensis (IC50 of 307.0 ± 79.6, 193.7 ± 44.3 and 81.8 ± 11.2 μg mL-1, respectively, after 24, 48 and 72 h of incubation). Then, in addition to its structural simplicity, riparin A revealed promising biological activities and remarkable in vitro leishmanicidal action, an important result in epidemiological point of view to control leishmaniasis in Brazil, including in the Amazon region.

Aniba riparia (Lauraceae) é uma importante planta medicinal encontrada na região amazônica que apresenta alcaloides do tipo alcamida e conhecidos como riparinas. Este trabalho teve como objetivo avaliar os efeitos antioxidantes, antitumorais e leishmanicidas in vitro da riparina A. Riparina A apresentou fraca capacidade antioxidante pelas técnicas do DPPH• (CE50 de 296,2 μg mL-1) e ABTS•+ (CE50 de 450,1 μg mL-1), mostrou moderada atividade contra carcinoma de cólon (HCT-116: CI50 de 21,7 μg mL-1) e atividade leishmanicida sobre formas promastigotas de Leishmania amazonensis (CI50 de 307,0 ± 79,6; 193,7 ± 44,3 e 81,8 ± 11,2 μg mL-1, respectivamente, após 24, 48 e 72 h de incubação). Assim, além de sua simplicidade estrutural, a riparina A revelou atividades biológicas promissoras e significativa ação leishmanicida in vitro, resultado importante diante da relevância epidemiológica para controle da leishmaniose no Brasil, inclusive na região amazônica.

Phenobarbital loaded microemulsion: development, kinetic release and quality control

ABSTRACT This study aimed to obtain and characterize a microemulsion (ME) containing phenobarbital (PB). The PB was incorporated in the proportion of 5% and 10% in a microemulsion system containing Labrasol(r), ethanol, isopropyl myristate and purified water. The physicochemical characterization was performed and the primary stability of the ME was evaluated. An analytical method was developed using spectrophotometry in UV  = 242 nm. The kinetics of the in vitro release (Franz model) of the ME and the emulsion (EM) containing PB was evaluated. The incorporation of PB into ME at concentrations of 5 and 10% did not change pH and resistance to centrifugation. There was an increase in particle size, a decrease of conductivity and a change in the refractive index in relation to placebo ME. The ME remained stable in preliminary stability tests. The analytical method proved to be specific, linear, precise, accurate and robust. Regarding the kinetics of the in vitro release, ME obtained an in vitro release profile greater than the EM containing PB. Thus, the obtained ME has a potential for future transdermal application, being able to compose a drug delivery system for the treatment of epilepsy.

RESUMO O objetivo deste trabalho foi obter e caracterizar uma microemulsão (ME) contendo fenobarbital (FEN). O FEN foi incorporado na proporção de 5% e 10% em um sistema microemulsionado composto por labrasol(r), etanol, miristato de isopropila e água purificada. Foi realizada a caracterização físico-química e avaliada a estabilidade preliminar da ME. Desenvolveu-se um método analítico por espectrofotometria em UV  = 242 nm. Foi avaliada a cinética de liberação in vitro (em modelo de Franz) da ME e da emulsão (EM) contendo FEN. A incorporação do FEN em ME nas concentrações de 5 e 10% não alterou o pH e a resistência à centrifugação. Houve aumento do tamanho da partícula, redução da condutividade e alteração do índice de refração em relação à ME placebo. A ME manteve-se estável nos ensaios de estabilidade preliminar. O método analítico demonstrou ser específico, linear, preciso, exato e robusto. Na cinética de liberação in vitro, a ME obteve um perfil de liberação in vitro superior a EM contendo FEN. Desta forma, a ME obtida tem potencial para uma futura aplicação transdérmica, podendo compor um sistema de liberação de fármacos para tratamento da epilepsia.

Ensaios pré-clínicos em ratos tratados com 1, 3-diestearil-2-oleilglicerol, constituinte isolado de Platonia insignis / Pre clinical trials in rats treated with 1, 3 -distearoyl-2-oleoylglycerol (TG1) constituent isolated from Platonia insignis

Introdução: Avaliou-se a toxicidade aguda de 1,3-diestearil-2-oleil-glicerol (TG1), composto obtido de Platonia insignis Mart. (bacurizeiro), após administração oral em ratos Wistar. Métodos: A toxicidade aguda foi analisada através dos parâmetros hematológicos e bioquímicos. A análise de citotoxicidade in vitro foi feita pelo método do sal 3-(4,5-dimetil-2-tiazol)-2,5-difenil-2-H-brometo de tetrazolium (MTT). Os tecidos cerebrais e hepáticos foram avaliados histopatologicamente. Resultados: O tratamento agudo com TG1(dose de 30 mg kg -1) não produziu alterações hematológicas e histopatológicas nas áreas cerebrais e hepáticas. A redução dos níveis das enzimas transaminase (AST) e fosfatase alcalina (ALKP) pode sugerir proteção hepática. As análises bioquímicas da aspartato aminotransferase, ALKP e do ácido úrico apresentaram seus níveis reduzidos, conferindo preservação dos rins e fígado dos animais (p<0,05). TG1 não revelou potencial citotóxico pelo método MTT. Conclusão: O tratamento com TG1 não produz alterações hematológicas, bioquímicas, histopatológicas cerebrais e hepáticas em ratos o que caracteriza uma baixa toxicidade.

Introduction: The aim of this study was to assess the acute toxicity of 1,3-distearoyl-2-oleoylglycerol (TG1), a compound isolated from Platonia insignis Mart. (bacurizeiro). Methods: The acute toxicity was analyzed by biochemical and hematological parameters. The cytotoxic study was conducted by the MTT method. The histopathological study was conducted in brain and liver tissues. Results: Acute treatment with TG1 (dose of 30 mg. kg -1) did not change the general behavior pattern of rats and not result in hematological and histological changes in the liver. The reduced levels of transaminase and alkaline phosphatase (ALKP) enzymes may suggest even certain liver protection. The biochemical analyzes demonstrated low levels of aspartate aminotransferase, ALKP and uric acid, providing preservation of kidneys and livers of animals (p<0.05). TG1 this study did not reveal cytotoxic potential by MTT method. Conclusion: These results indicate that treatment with TG1 not produce hematological, biochemical and histopathological alterations in rats suggesting low toxicity

Serum Oxidative Stress Markers and Genotoxic Profile Induced by Chemotherapy in Patients with Breast Cancer: A Pilot Study.

The aim of this study was to evaluate the oxidative parameters of erythrocytes and genotoxicity in leukocytes of patients with breast cancer. Oxidative parameters were detected by spectrophotometry and genotoxic damage by single cell gel electrophoresis. Twenty-eight women with breast cancer were monitored before chemotherapy and after the second and fourth cycles of therapy with cyclophosphamide and doxorubicin. After the fourth cycle, increases (P < 0.05) in the reactive substances to thiobarbituric acid levels, nitrite content, and superoxide dismutase activity and high rates of DNA damage in leukocytes were observed when compared with healthy women group and baseline levels. Similarly, after the second cycle, the same parameters were increased (P < 0.05) when compared with baseline levels. Increase in catalase activity was detected only after the fourth cycle and reduced glutathione levels and glutathione peroxidase activity were decreased in all cycles when compared with healthy women, as well as after the second and fourth chemotherapy cycles compared to baseline (P < 0.05). Patients with breast cancer presented an indicative of oxidative stress before, during, and after chemotherapy, as well as increased genotoxic damage in all stages of treatment, demonstrating the clinical applicability of this investigation.

Diminazene aceturate--An antiparasitic drug of antiquity: Advances in pharmacology & therapeutics.

Diminazene aceturate (C14H15N7.2C4H7NO3) is an aromatic diamidine that was developed more than six decades ago and has been marketed until today for the control of trypanosomiasis. In recent years, however, this trypanocidal compound has been extensively studied with respect to its therapeutic potential and has consequently attracted much interest for the development of further research. The objective of this study was to conduct a systematic review on diminazene aceturate regarding its pharmacological properties. In this way, databases were searched for articles (ScienceDirect, Scopus, PubMed, Web of Science and SciFinder) and patents (INPI, USPTO, WIPO, DPMA, SIPO, DERWENT, CIPO and EPO). For the development of this review, 115 articles and 22 patents were selected and analyzed. It was thus possible to highlight several researches that have investigated alternatives in order to improve success in the treatment of animal trypanosomiasis, by using new drugs in associations with diminazene aceturate, as well as looking for new pharmacological applications for this compound, such as leishmanicidal, amebicidal, anti-pneumocystis, anti-rheumatoid arthritis, antihypertensive agent, and mainly as an activator of angiotensin-converting enzyme 2. Another pharmacological property still little studied is the inhibition of acid-sensitive ion channels (ASIC1a, ASIC1b, ASIC2a and ASIC3), which are related to the development of various diseases. Collectively, these studies conducted by several research groups extend the use of diminazene aceturate beyond the antitrypanosomal activity and suggest promising new applications.

Counteracting effects on free radicals and histological alterations induced by a fraction with casearins.

Casearia sylvestris Swartz is a medicinal plant widely distributed in Brazil. It has anti-inflammatory, antiulcer and antitumor activities and is popularly used to treat snakebites, wounds, diarrhea, flu and chest colds. Its leaves are rich in oxygenated tricyclic cis-clerodane diterpenes, particulary casearins. Herein, we evaluated the antioxidant activities of a fraction with casearins (FC) isolated from C. sylvestris and histological changes on the central nervous system and livers of Mus musculus mice. Firstly, in vitro studies (0.9, 1.8, 3.6, 5.4 and 7.2 µg/mL) revealed EC50 values of 3.7, 6.4 and 0.16 µg/mL for nitrite, hydroxyl radical and TBARS levels, respectively. Secondly, FC (2.5, 5, 10 and 25 mg/kg/day) was intraperitoneally administered to Swiss mice for 7 consecutive days. Nitrite levels in the hippocampus (26.2, 27.3, 30.2 and 26.6 µM) and striatum (26.3, 25.4, 34.3 and 27.5 µM) increased in all treated animals (P < 0.05). Lower doses dropped reduced glutathione, catalase and TBARS levels in the hippocampus and striatum. With the exception of this reduction in TBARS formation, FC displayed only in vitro antioxidant activity. Animals exhibited histological alterations suggestive of neurotoxicity and hepatotoxicity, indicating the need for precaution regarding the consumption of medicinal formulations based on Casearia sylvestris.

Phytol in a pharma-medico-stance.

This study aims to review phytol (PYT), through published articles, periodicals, magazines and patents, which were retrieved from the PM, SD, WS, SP; DII, WIPO, CIPO, USPTO and INPI databases. Among the 149 articles and 62 patents, 27.52% articles and 87.09% patients were found on the searched topic, PYT and its sources and synthesis and metabolism; then followed by 15.44% and 14.77% articles on PYT in cytotoxicity/cancer/mutagenicity/teratogenicity and PYT in neurological diseases, respectively. In the pharma-medico viewpoint, PYT and its derivatives have been evident to have antimicrobial, cytotoxic, antitumorous, antimutagenic, anti-teratogenic, antibiotic-chemotherapeutic, antidiabetic, lipid lowering, antispasmodic, anticonvulsant, antinociceptive, antioxidant, anti-inflammatory, anxiolytic, antidepressant, immunoadjuvancy, hair growth facilitator, hair fall defense and antidandruff activities. Otherwise, the important biometebolite of PYT is phytanic acid (PA). Evidence shows PA to have cytotoxic, anticancer, antidiabetic, lipid lowering and aniteratogenic activities. In addition, it may be considered as an important biomarker for some diseases such as Refsum's Disease (RD), Sjögren Larsson syndrome (SLS), rhizomelic chondrodysplasia punctata (RZCP), chronic polyneuropathy (CP), Zellweger's disease hyperpipecolic academia (ZDHA) and related diseases. Thus, phytol may be considered as a new drug candidate.

HFE gene mutation and oxidative damage biomarkers in patients with myelodysplastic syndromes and its relation to transfusional iron overload: an observational cross-sectional study.

OBJECTIVE: A relation between transfusional IOL (iron overload), HFE status and oxidative damage was evaluated. DESIGN, SETTING AND PARTICIPANTS: An observational cross-sectional study involving 87 healthy individuals and 78 patients with myelodysplastic syndromes (MDS) with and without IOL, seen at University Hospital of the Federal University of Ceará, Brazil, between May 2010 and September 2011. METHODS: IOL was defined using repeated measures of serum ferritin ≥1000 ng/mL. Variations in the HFE gene were investigated using PCR/restriction fragment length polymorphism (RFLP). The biomarkers of oxidative stress (plasmatic malonaldehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD)) were determined by spectrophotometry. RESULTS: The HFE gene variations were identified in 24 patients (30.77%) and 5 volunteers (5.74%). The H63D variant was observed in 35% and the C282Y variant as heterozygous in 5% of patients with MDS with IOL. One patient showed double heterozygous variant (C282Y/H63D) and serum ferritin of 11,649 ng/mL. In patients without IOL, the H63D variant was detected in 29.34%. Serum MDA levels were highest in patients with MDS with IOL, with a significant difference when compared with patients without IOL and healthy volunteers, pointing to the relationship between IOL and oxidative stress. The GPx and SOD were also significantly higher in these patients, indicating that lipid peroxidation increase was followed by an increase in antioxidant capacity. Higher ferritin levels were observed in patients with HFE gene variation. 95.7% of patients with MDS with the presence of HFE gene variations had received more of 20 transfusions. CONCLUSIONS: We observed a significant increase in MDA levels in patients with MDS and IOL, suggesting an increased lipid peroxidation in these patients. The accumulation of MDA alters the organisation of membrane phospholipids, contributing to the process of cellular degeneration. Results show that excess iron intensifies the process of cell damage through oxidative stress. TRIAL REGISTRATION NUMBER: Local Ethics Committee (licence 150/2009).

The role of flavonoids on oxidative stress in epilepsy.

BACKGROUNDS: Oxidative stress can result from excessive free-radical production and it is likely implicated as a possible mechanism involved in the initiation and progression of epileptogenesis. Flavonoids can protect the brain from oxidative stress. In the central nervous system (CNS) several flavonoids bind to the benzodiazepine site on the GABAA-receptor resulting in anticonvulsive effects. OBJECTIVE: This review provides an overview about the role of flavonoids in oxidative stress in epilepsy. The mechanism of action of flavonoids and its relation to the chemical structure is also discussed. RESULTS/CONCLUSIONS: There is evidence that suggests that flavonoids have potential for neuroprotection in epilepsy.

In vivo evaluation of anticonvulsant and antioxidant effects of phenobarbital microemulsion for transdermal administration in pilocarpine seizure rat model.

This study aimed to evaluate a microemulsion system (ME) containing phenobarbital in epilepsy model induced by pilocarpine in rats and to oxidative stress and histologic lesions in hippocampus. The microemulsion was applied to the shaved back of Wistar rats. The animals were divided into the following groups: control group (P400); ME50 40mg/kg, topically-t.p.; ME100, 40mg/kg, t.p.; EM50, 40mg/kg, t.p.; phenobarbital solution 40mg/kg (PS), oral. After 60min, behavioral changes were evaluated for 1h in the model of epileptical crisis induced by pilocarpine. Phenobarbital in microemulsion was able to increase the latency for status epilepticus (SE) (p<0.05), decrease the number of epileptical crisis (ME50: p<0.001; ME100: p<0.01) and decrease mortality rate by 80% compared to P400. In EM50 and PS groups, deaths were decreased by 53.3% and 100% respectively. The ME50 and ME100 groups were able to reduce oxidative stress in experimental animals when compared to the P400. The microemulsion was still capable of reducing neuronal damage in the hippocampal areas. The results of this study come in an innovative way, demonstrating the ability of transdermal ME50 and ME100 to reduce pilocarpine-induced epileptical crisis, oxidative stress, besides neuronal damages.

Acute toxicity and anticonvulsant activity of liposomes containing nimodipine on pilocarpine-induced seizures in mice.

Nimodipine has been shown to have an inhibitory action on seizures and brain damage in rodents. However, the pharmaceutical applicability of this drug is limited by its low solubility in gastrointestinal fluids and high first-pass effect in the liver, which leads to low bioavailability. These difficulties can be overcome through the use of liposomes. The aim of the present study is to evaluate the toxicity and anticonvulsant activity of liposomes containing nimodipine (NMD-Lipo) on pilocarpine-induced seizures. NMD-Lipo was prepared using the lipid-film hydration method. Central nervous system toxicity of NMD-Lipo was assessed by Hippocratic screening. Systemic toxicity was evaluated by analyses of biochemical and hematological parameters and by observing possible signs of toxicity. The possible anticonvulsant activity was tested by the pilocarpine model. The administration of the NMD-Lipo at doses of 0.1, 1, and 10 mg/kg caused no toxicity in animals. Furthermore, NMD-Lipo prevented the installation of 100% of the pilocarpine-induced seizures and prevented the death of 100% of the mice treated with pilocarpine. These data shown that NMD-Lipo has an anticonvulsant activity significantly superior to free NMD, suggesting that the liposomes promoted a drug controlled release by improving its bioavailability and consequently increasing its pharmacological activity.

Spectroscopic studies on the in vitro antioxidant capacity of isopentyl ferulate.

Essential oils have played a prominent role in research on natural products, due to the high level of bioactive constituents, which include those derived from phenylpropanoids or terpenoids. This study aimed to evaluate the antioxidant capacity of isopentyl ferulate (IF) employing in vitro experimental models for elimination of the 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS+), hydroxyl (OH) and nitric oxide (NO), as well as its capacity to electron transfer by reducing potential and inhibition of lipid peroxidation by TBARS (thiobarbituric acid reactive substances) method. In all in vitro antioxidants protocols, isopentyl ferulate showed to be potent in a concentration of 54.4 nM, presenting a percentage inhibition of 91.29±0.57, 92.63±0.28, 83.62±0.18, 77.07±0.72 and 79.51±0.32% for DPPH, ABTS+, hydroxyl, nitric oxide and TBARS level, respectively. The increase of absorbance at 700 nm in the concentrations of 3.4, 6.8, 13.6, 27.2 and 54.4 nM shows the reducing potential of IF. Similar results were obtained with Trolox (559 nM), a hydrophilic synthetic analogue of α-tocopherol, which is widely used as a standard antioxidant. The present study demonstrated that isopentyl ferulate has an antioxidant activity in vitro experimental models, suggesting that this compound could enhance the development of a new product with antioxidant properties. However, further in vivo studies are needed to assign possible implications in the treatment of diseases related with free radicals.

Neuropharmacological effects of carvacryl acetate on δ-aminolevulinic dehydratase, Na+, K+-ATPase activities and amino acids levels in mice hippocampus after seizures.

Epileptic syndromes are highly prevalent neurological conditions and can often be disabling. In order to find an alternative for treatment, this study evaluated anticonvulsant effects of carvacryl acetate (CA), a derivative of monoterpene carvacrol, after seizures induced by pilocarpine (P400), picrotoxin (PIC) or pentylenetetrazol (PTZ). We also analyzed the CA effects on Na+, K+-ATPase and δ-aminolevulinic acid dehydratase (δ-ALA-D) activities in hippocampus mice after seizures induced by P400, PIC or PTZ. In addition, glutamate, δ-aminobutyric acid (GABA), glutamine and aspartate levels in mice hippocampus treated with CA after seizures induced by P400, PIC or PTZ were also measured. CA produced anticonvulsant effects against seizures induced by P400, PIC or PTZ, and its effects were reversed by flumazenil, suggesting that action mechanism can be mediated by GABAergic system. CA increased GABA levels, but did not alter glutamate and aspartate concentrations in mice hippocampus after seizures induced by P400, PIC or PTZ when compared with seizures induced by P400, PIC or PTZ (p<0.05), respectively, as well as decreased glutamine content in mice hippocampus after seizures induced by PIC when compared with seizures induced by PIC (p<0.05). In addition, CA also increased Na+, K+-ATPase and δ-aminolevulinic acid dehydratase activities after seizures induced by P400, PIC or PTZ when compared with seizures induced by P400, PIC or PTZ (p<0.05), respectively. This study demonstrated that CA could be a future therapeutic option for treatment of epilepsy, with a multifactorial brain action mechanism.

Evaluation of p-cymene, a natural antioxidant.

CONTEXT: Several studies have demonstrated that essential oils and their major components have antioxidant activity. p-Cymene is a monoterpene and a major constituent of essential oils of various species of plants. OBJECTIVE: This paper evaluated the antioxidant potential of p-cymene in the hippocampus of mice by determining the levels of thiobarbituric acid reactive substances (TBARS), nitrite content, and activity of catalase (CAT) and superoxide dismutase (SOD). MATERIALS AND METHODS: Swiss mice were intraperitoneally treated with 0.05% Tween 80 dissolved in 0.9% saline solution, ascorbic acid 250 mg/kg, and p-cymene at doses of 50, 100, and 150 mg/kg, respectively. After treatment, all groups were observed for 24 h, afterwards, the groups were euthanized for removal of the brain and dissection of the hippocampus. RESULTS: The results of treatment with p-cymene were a significant decrease in lipid peroxidation and nitrite content at a dose of CYM 50: 65.54%, CYM 100: 73.29%, CYM 150: 89.83%, and CYM 50: 71.21%; CYM 100: 68.61% and CYM 150:67%, respectively, when compared with the control group. The results showed that at all tested doses, p-cymene produces an increase in SOD and catalase activity significantly at a dose of CYM 50: 22.7%, CYM 100: 33.9%, CYM 150: 63.1%, and CYM 50: 119.25%, CYM 100: 151.83% and CYM 150: 182.70%, respectively, when compared with the vehicle-treated group. DISCUSSION AND CONCLUSION: The result of this study shows that p-cymene has an antioxidant potential in vivo and may act as a neuroprotective agent in the brain. This compound may present a new strategy in the development of treatment for many diseases in which oxidative stress plays an important pathophysiological role.

Behavioral tests and oxidative stress evaluation in mitochondria isolated from the brain and liver of mice treated with riparin A.

AIMS: This study aimed at evaluating the oxidative stress in mitochondria isolated from the brain and liver of mice treated with riparin A, as well as the locomotor activity and myorelaxant effect of this compound. Behavioral models of rota rod and open field tests were used for locomotor activity and myorelaxant effect evaluation. MAIN METHODS: The animals were divided into five groups (n=8), which were treated with: diazepam (1mg/kg, i.p), riparin A (5, 10, and 20mg/kg, o.r.) or vehicle (0.9% saline, o.r.). The oxidative stress evaluation was carried out in mitochondria isolated from the brain and liver of mice from five experimental groups (n=8), which were treated with: ascorbic acid (250 mg/kg; positive control), vehicle (0.9% saline; negative control) and riparin A (5, 10 and 20mg/kg). KEY FINDINGS: In an open field and rota rod test a significant difference in the number of crossings, in time of permanence on the swivel bar and in the number of falls in riparin A treated animals (5, 10 and 20mg/kg) was not observed, when compared with negative control (vehicle) (p>0.05). In comparison to the negative control, there was a reduction of lipid peroxidation levels and nitrite content in mice treated with riparin A (p<0.05). Reduced glutathione (GSH) levels (p<0.05), superoxide dismutase (SOD) and catalase activities increased in the brain (rip A 5mg/kg; p<0.05), while in the liver SOD remained unchanged (p>0.05) and catalase activity (p<0.05) was reduced. SIGNIFICANCE: Riparin A was presented as a bioactive molecule devoid of adverse effects of alteration of motor activity.