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.

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.

Is there a correlation between in vitro antioxidant potential and in vivo effect of carvacryl acetate against oxidative stress in mice hippocampus?

This study investigated in vitro and in vivo antioxidant potential of carvacryl acetate (CA), a derivative of carvacrol, monoterpenic component of oregano. The correlation between in vitro and in vivo CA effects was also determined. In vitro tests measured thiobarbituric acid reactive species content, nitrite formation and hydroxyl radical levels. In vivo tests measured thiobarbituric acid reactive species content, nitrite concentration and reduced glutathione (GSH) levels, as well as glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase activities were measured, using mice hippocampus. The CA administrations for in vivo tests were intraperitoneally and acutely improved. CA reduced lipid peroxidation, nitrite and hydroxyl radical contents in vitro as well as lipid peroxidation and nitrite content in vivo. It also increased reduced GSH levels and GPx as well as catalase activities. Moreover, CA required a lower concentration to inhibit 50 % of free radicals measured in vitro than trolox. There was significant negative correlation between in vitro nitrite levels and in vivo reduced GSH levels; in vitro nitrite content and in vivo GPx activity as well as in vitro hydroxyl radical levels and in vivo SOD activity. To date, this is the first study which suggests vitro and in vivo antioxidant potential to this monoterpene and the correlation between these parameters.

Antioxidant effects of nerolidol in mice hippocampus after open field test.

The aim of this study was to evaluate the neuroprotective effects of nerolidol in mice hippocampus against oxidative stress in neuronal cells compared to ascorbic acid (positive control) as well as evaluated the nerolidol sedative effects by open field test compared to diazepam (positive control). Thirty minutes prior to behavioral observation on open field test, mice were intraperitoneally treated with vehicle, nerolidol (25, 50 and 75 mg/kg), diazepam (1 mg/kg) or ascorbic acid (250 mg/kg). To clarify the action mechanism of of nerolidol on oxidative stress in animals subjected to the open field test, Western blot analysis of Mn-superoxide dismutase and catalase in mice hippocampus were performed. In nerolidol group, there was a significant decrease in lipid peroxidation and nitrite levels when compared to negative control (vehicle). However, a significant increase was observed in superoxide dismutase and catalase activities in this group when compared to the other groups. Vehicle, diazepam, ascorbic acid and nerolidol groups did not affected Mn-superoxide dismutase, catalase mRNA or protein levels. Our findings strongly support the hypothesis that oxidative stress occurs in hippocampus. Nerolidol showed sedative effects in animals subjected to the open field test. Oxidative process plays a crucial role on neuronal pathological consequence, and implies that antioxidant effects could be achieved using this sesquiterpene.

Anthelmintic activity of carvacryl acetate against Schistosoma mansoni.

Blood flukes of the genus Schistosoma are the causative agents of human schistosomiasis, a debilitating disease that afflicts over 200 million people worldwide. Praziquantel is the drug of choice but concerns over praziquantel resistance have renewed interest in the search for alternative drug therapies. Carvacrol, a naturally occurring monoterpene phenol and food additive, has been shown high medicinal importance, including antimicrobials activities. The aim of this study was to evaluate in vitro effect of carvacryl acetate, a derivative of carvacrol, on Schistosoma mansoni adult worms. We demonstrated that carvacryl acetate at 6.25 µg/mL has antischistosomal activity, affecting parasite motility and viability. Additionally, confocal laser scanning microscopy pictures revealed morphological alterations on the tegumental surface of worms, where some tubercles appeared to be swollen with numerous small blebs emerging from the tegument around the tubercles. Furthermore, experiments performed using carvacryl acetate at sub-lethal concentrations (ranging from 1.562 to 6.25 µg/mL) showed an inhibitory effect on the daily egg output of paired adult worms. Thus, carvacryl acetate is toxic at high doses, while at sub-lethal doses, it significantly interferes with the reproductive fitness of S. mansoni adult worms. Due to its safety and wide use in the industry, carvacryl acetate is a promising natural product-derived compound and it may represent a step forward in the search for novel anthelmintic agents, at a time when there is an urgent need for novel drugs.

Anticonvulsant and antioxidant effects of cyano-carvone and its action on acetylcholinesterase activity in mice hippocampus.

The anticonvulsant effect of cyano-carvone, a monoterpene monocyclic, was investigated in epilepsy model induced by pilocarpine. Cyano-carvone at doses of 25, 50 or 75 mg/kg promoted a reduction of 16.7, 33 and 66.7%, respectively, against pilocarpine-induced seizures, and it was efficacious in increasing both the latency to first seizures and the survival percentage, resulting in 33.3, 67 and 91.7% of protection against death induced by seizures, respectively (P < 0.05). The reference drug atropine (25 mg/kg) also produced a significant protection (100%). Its monoterpene, at 25, 50 and 75 mg/kg, was also capable to increase the latency for installation of status epilepticus induced by pilocarpine, and presented a significant protection against lipid peroxidation and nitrite formation in mice hippocampus (P < 0.05). In addition, it was observed that the cyano-carvone pretreatment increased the acetylcholinesterase activity in mice hippocampus after pilocarpine-induced seizures. The present results clearly indicate the anticonvulsant ability of cyano-carvone, which can be, at least in part, explained by the increased activity of the acetylcholinesterase enzyme. Our data suggest that the action mechanism can also be due to a direct activation of the antioxidant enzymes that could be associated with a reduction observed in oxidative stress in mice hippocampus, probably involving an inhibition of free radical production.

Superoxide dismutase and catalase activities in rat hippocampus pretreated with garcinielliptone FC from Platonia insignis.

CONTEXT: Platonia insignis Mart. (Clusiaceae), commonly known as "bacuri," is a timber and fruit native species of the Brazilian Amazon. Some plants of the Clusiaceae family have their pharmacological properties associated with the presence of xanthone and polycyclic polyprenylated acylphloroglucinols derivatives, which have antioxidant and anticarcinogenic activities. OBJECTIVE: The aim of this study was to assess the in vivo potential of extracts, fractions, and garcinielliptone FC isolated from of Platonia insignis seeds as a natural antioxidant. MATERIALS AND METHODS: Male Wistar rats (250-280 g; 2 months old) were treated with Tween 80 0.05% dissolved in 0.9% saline (i.p, vehicle - control group), ethanol extract (EE), hexane extract (HE), dichloromethane fraction (DMF), ethyl acetate fraction (EAF), and garcinielliptone FC (GFC) isolated from P. insignis at doses 2 mg/kg (i.p.). All groups were observed for 24 h after the treatment. The antioxidant enzymatic activities [superoxide dismutase (SOD) and catalase (CAT)] were measured using spectrophotometric methods. RESULTS: There were no marked alterations in SOD and CAT activities in rat hippocampus after pretreatment with EE, HE, DMF, EAF, and GFC. However, the pretreatment with GFC induced a significantly increase of 13, 17, 19, and 13% in SOD activities when compared to EE, HE, DMF, or EAF groups, respectively. DISCUSSION AND CONCLUSION: Our findings strongly support the hypothesis that GFC isolated from P. insignis has a significant potential to be used as a natural antioxidant agent probably due to the modulation of enzymatic activity of hippocampal SOD.

Antioxidant and antinociceptive effects of Citrus limon essential oil in mice.

The antioxidant and antinociceptive activities of Citrus limon essential oil (EO) were assessed in mice or in vitro tests. EO possesses a strong antioxidant potential according to the scavenging assays. Moreover, it presented scavenger activity against all in vitro tests. Orally, EO (50, 100, and 150 mg/kg) significantly reduced the number of writhes, and, at highest doses, it reduced the number of paw licks. Whereas naloxone antagonized the antinociceptive action of EO (highest doses), this suggested, at least, the participation of the opioid system. Further studies currently in progress will enable us to understand the action mechanisms of EO.

Evaluation of possible antioxidant and anticonvulsant effects of the ethyl acetate fraction from Platonia insignis Mart. (Bacuri) on epilepsy models.

The aim of present study was to examine the effects of the ethyl acetate fraction (EAF) from Platonia insignis on lipid peroxidation level, nitrite formation, and superoxide dismutase and catalase activities in rat striatum prior to pilocarpine-induced seizures as well as to explore its anticonvulsant activity in adult rats prior to pentylenetetrazole (PTZ)- and picrotoxin (PIC)-induced seizures. Wistar rats were treated with vehicle, atropine (25mg/kg), EAF (0.1, 1, and 10mg/kg), pilocarpine (400mg/kg, P400 group), PTZ (60 mg/kg, PTZ group), PIC (8 mg/kg, PIC group), atropine+P400, EAF+P400, EAF+PTZ, or EAF+PIC. Significant decreases in number of crossings and rearings were observed in the P400 group. The EAF 10+P400 group also had significant increases in these parameters. In addition, in rats treated with P400, there were significant increases in lipid peroxidation and nitrite levels; however, there were no alterations in SOD and catalase activities. In the EAF 10+P400 group, lipid peroxidation and nitrite levels significantly decreased and SOD and catalase activities significantly increased after pilocarpine-induced seizures. Additionally, effects of the EAF were evaluated in PTZ and PIC models. EAF did not increase the latency to development of convulsions induced with PTZ and PIC at the doses tested. Our findings strongly support the hypothesis that EAF does not have anticonvulsant activity in the different models of epilepsy studied. Our results indicate that in the in vivo model of pilocarpine-induced seizures, EAF has antioxidant activity, but not anticonvulsant properties at the doses tested.

Caffeic acid effects on oxidative stress in rat hippocampus after pilocarpine-induced seizures.

The objective of the study was to evaluate the caffeic acid (CA) effects against the oxidative stress (OS) observed during seizures. Wistar rats were intraperitoneally treated with either 0.9% saline (control), CA (4 mg/kg), pilocarpine (400 mg/kg, pilocarpine group), or the association of CA (4 mg/kg) plus pilocarpine (400 mg/kg). The thiobarbituric-acid-reacting substances and the hippocampal nitrite content were significantly increased (89 and 94%, respectively) in pilocarpine group when compared with control. There were marked decreases in lipid peroxidation level (43%) and nitrite content (45%) in CA group when compared with pilocarpine group. There were no marked alterations in superoxide dismutase (SOD) and catalase (CAT) activities in pilocarpine group; however, the SOD and CAT activities were significantly increased (35 and 51%, respectively) after CA pretreatment. Our findings strongly support the hypothesis that OS was indeed generated in hippocampus. CA pretreatment can reduces the OS produced by seizures.

Antioxidant activity of Citrus limon essential oil in mouse hippocampus.

CONTEXT: Citrus limon (L.) Burms (Rutaceae) has been shown in previous studies to have various biological functions (anti-inflammatory, antiallergic, antiviral, antimutagenic, and anticarcinogenic). However, traditional uses in folk medicine suggest that C. limon may have an effect on the central nervous system (CNS). OBJECTIVE: This study investigated the effects of C. limon essential oil (EO) on lipid peroxidation level, nitrite content, glutathione reduced (GSH) concentration, and antioxidant enzymes [superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx)] activities in mice hippocampus. MATERIALS AND METHODS: Swiss mice were treated with the suspension of 0.5% Tween 80, in distilled water used as vehicle (i.p., control group) and with EO in three different doses (0.05, 0.1, or 0.15 g/kg, i.p., EO 50, EO 100, and EO 150 groups, respectively). After the treatments, all groups were observed for 24 h. The enzyme activities as well as the lipid peroxidation, nitrite, and GSH concentrations in mice hippocampus were measured using spectrophotometric methods and the results were compared with values obtained from control group. RESULTS: EO of C. limon treatment significantly reduced the lipid peroxidation level and nitrite content but increased the GSH levels and the SOD, catalase, and GPx activities in mice hippocampus. DISCUSSION AND CONCLUSION: Our findings strongly support the hypothesis that oxidative stress in hippocampus can occur during neurodegenerative diseases, proving that hippocampal damage induced by the oxidative process plays a crucial role in brain disorders, and also imply that a strong protective effect could be achieved using EO of C. limon as an antioxidant.

Lipoic acid alters delta-aminolevulinic dehydratase, glutathione peroxidase and Na+,K+-ATPase activities and glutathione-reduced levels in rat hippocampus after pilocarpine-induced seizures.

In the present study, we investigated the effects of lipoic acid (LA) in the brain oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), lipoic acid (10 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of LA (10 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before the administration of LA (LA plus pilocarpine group). After the treatments, all groups were observed for 1 h. The enzyme activities [delta-aminolevulinic dehydratase (delta-ALA-D), glutathione peroxidase (GPx), glutathione reductase (GR), and Na+,K+-ATPase] as well as the glutathione-reduced (GSH) and ascorbic acid (AA) concentrations were measured using spectrophotometric methods, and the results were compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA were also evaluated on the same parameters. In pilocarpine group, no changes were observed in GPx and GR activities and AA content. Moreover, in the same group, decrease in GSH levels as well as a reduction in delta-ALA-D and Na+,K+-ATPase activities after seizures was observed. In turn, in LA plus pilocarpine group, the appearance of seizures was abolished, and the decreases in delta-ALA-D and Na+,K+-ATPase activities produced by seizures as well as increases in GSH levels and GPx activity were reversed, when compared to the pilocarpine seizing group. The results of the present study demonstrated that preadministration of LA abolished seizure episodes induced by pilocarpine in rat, probably by reducing oxidative stress in rat hippocampus caused by seizures.

Pilocarpine-induced seizures produce alterations on choline acetyltransferase and acetylcholinesterase activities and deficit memory in rats.

In the present study, we investigated the effect of seizures on rat performance in the Morris water maze task, as well as on choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in rat hippocampus. Wistar rats were treated with 0.9% saline (i.p., control group) and pilocarpine (400 mg/kg, i.p., pilocarpine group). After the treatments all groups were observed for 1 h. The changes on reference and working spatial memory caused by pilocarpine administration were observed in seized rats. The ChAT and AChE activities were measured using spectrophotometric methods and the results compared to values obtained from saline animals. Its activities were also determined after behavioral task. Results showed that seizures alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant day's effect with significant differences between control and pilocarpine-induced seizures. In pilocarpine group, it was observed a significant decreased in ChAT and AChE activities, when compared to control group. Our findings suggest that seizures caused cognitive dysfunction and a decrease of ChAT and AChE activities that might be related, at least in part, to the neurological problems presented by seizures induced by pilocarpine.

Lipoic Acid increases hippocampal choline acetyltransferase and acetylcholinesterase activities and improvement memory in epileptic rats.

In the present study we investigated the effect of seizures on rat performance in the Morris water maze task, as well as on choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in rat hippocampus. Wistar rats were treated with 0.9% saline (i.p., control group), lipoic acid (20 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of LA (20 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of LA (LA plus pilocarpine group). After the treatments all groups were observed for 1 h. The effect of lipoic acid administration was observed on reference and working spatial memory of seized rats. The ChAT and AChE activities were measured using spectrophotometric methods and the results compared to values obtained from saline and pilocarpine-treated animals. Its activity was also determined after behavioral task. Results showed that pretreatment with lipoic acid did not alter reference memory when compared to saline-treated animals. In the working memory task, we observed a significant day's effect with significant differences between control and pilocarpine-induced seizures and pretreated animals with lipoic acid. In LA plus pilocarpine group was observed a significantly increased in ChAT and AChE activities, when compared to pilocarpine group. Results showed that acute administration of lipoic acid alone did not alter hippocampal ChAT and AChE activities. Our findings suggest that seizures caused cognitive dysfunction and a decrease of ChAT and AChE activities that might be related, at least in part, to the neurological problems presented by epileptic patients. Lipoic acid can reverse cognitive dysfunction observed in seized rats as well as increase the ChAT and AChE activities in hippocampus of rats prior to pilocarpine-induced seizures, suggesting that this antioxidant could be used in clinic treatment of epilepsy.

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.

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.

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.

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.

Protective effects of N-acetylserotonin against 6-hydroxydopamine-induced neurotoxicity.

The present work studied in vivo neuroprotective effects of n-acetylserotonin (NAS), the immediate precursor of melatonin, on the dopaminergic system, in rats lesioned with the unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA). Two weeks after the lesion, the dopamine receptor agonist, apomorphine, produced rotational asymmetry, and the NAS treatment significantly reduced the motor deficit following the apomorphine challenge. The apomorphine-induced rotational behavior was blocked by 84, 86 and 53% after NAS, at doses of 2, 5 and 10 mg/kg, i.p., respectively. The injection of 6-OHDA significantly decreased DA, DOPAC and HVA levels in the rat striatum. In contrast, the NAS (2, 5 and 10 mg/kg, i.p., daily for 7 days) treatment partially reversed the decreases caused by 6-OHDA, and the neurotransmitter levels were brought to approximately 50% of that observed in the contralateral sides. NAS was more efficient at the smaller doses. NAS (5 mg/kg) produced an up-regulation of D1 (37%) and D2 (37%) receptors associated with a decrease in Kd values.