Exploring the leishmanicidal potential of terpenoids: a comprehensive review on mechanisms of cell death.

Leishmaniasis is a neglected tropical disease with a wide spectrum of clinical manifestations, ranging from visceral to cutaneous, with millions of new cases and thousands of deaths reported each year. The species of Leishmania and the immune response of the host determine the severity of the disease. Leishmaniasis remains challenging to diagnose and treat, and there is no vaccine available. Several studies have been conducted on the use of herbal medicines for the treatment of leishmaniasis. Natural products can provide an inexhaustible source of chemical diversity with therapeutic potential. Terpenes are a class of natural products derived from a single isoprene unit, a five-carbon compound that forms the basic structure of isoprenoids. This review focuses on the most important and recent advances in the treatment of parasites of the genus Leishmania with different subclasses of terpenes. Several mechanisms have been proposed in the literature, including increased oxidative stress, immunomodulatory role, and induction of different types of parasite cell death. However, this information needs to be brought together to provide an overview of how these compounds can be used as therapeutic tools for drug development and as a successful adjuvant strategy against Leishmania sp.

Natural product-based nanomedicine applied to fungal infection treatment: A review of the last 4 years.

Fungal infections are one of the main public health problems, especially in immunocompromised patients, nosocomial environments, patients with chronic diseases, and transplant recipients. These diseases are increasingly frequent and lethal because the microorganism has a high capacity to acquire resistance to available therapy. The main resistance factors are the emergence of new strains and the uncontrolled use of antifungals. It is, therefore, important to develop new methods that contribute to combating fungal diseases in the clinical area. Natural products have considerable potential for the development of new drugs with antifungal activity, mainly due to their biocompatibility and low toxic effect. This promising antimicrobial activity of natural products is mainly due to the presence of flavonoids, terpenes, and quinones, which explains their antifungal potential. Pharmaceutical nanotechnology has been explored to enhance the delivery, selectivity, and clinical efficacy of these products. Nanotechnological systems provide a safe and selective environment for various substances, such as natural products, improving antifungal activity. However, further safety experiments (in vivo or clinical trials) need to be carried out to prove the therapeutic action of natural products, since they may have undesirable, toxic, and mutagenic effects. Therefore, this review article addresses the main nanotechnological methods using natural products for effective future treatment against the main fungal diseases.

Effects of terpenes in the treatment of visceral leishmaniasis: A systematic review of preclinical evidence.

Visceral leishmaniasis (VL) is a severe and potentially fatal neglected tropical disease, being considered a public health concern in many countries worldwide. There are still no vaccines against human VL, and the existing chemotherapy is often toxic. Thereby, alternative treatments have been investigated, and byproducts from plant metabolism have been a source of promising pharmacological compounds. Terpenes are secondary metabolites that exhibit a large spectrum of therapeutic activities. Herein, we conducted a systematic review to evaluate the effects of terpenes in the treatment of VL in rodents. After an extensive search using the PubMed/MEDLINE, Scopus, and Web of Science databases, we included 34 articles in this review. Our results revealed that triterpenes were the most used terpenes by the eligible studies. Overall, terpene treatment showed no or negligible toxicity, causing an increase in the Th1-type immune response profile and nitric oxide production. It also reduced the Th2 cytokines levels and parasite load (> 90% to > 99%). Moreover, terpenes induced apoptosis by damaging the plasma membrane and inhibiting DNA topoisomerases in the parasite. The use of terpene carriers increased the terpene bioavailability in the body, preventing their rapid excretion and promoting the drug delivery at the site of Leishmania infection. Terpene derivatives showed better pharmacokinetics than the original terpenes. Altogether, the benefits of VL treatment with terpenes in preclinical studies may open new directions for other preclinical and human trials.

The antimicrobial effect behind Cannabis sativa.

The development of multidrug-resistant bacteria has revealed the need for new antimicrobial compounds. Cannabis sativa preparations have a long history of medical applications, including the treatment of infectious diseases. This review collects the information about the activity of C. sativa extracts and its main components (cannabinoids and terpenes) against pathogenic bacteria and fungus, to assess its potential using as antimicrobial agents.

Plant Terpenes on Treating Cardiovascular and Metabolic Disease: A Review.

The use of medicinal plants as a therapy alternative is old as human existence itself. Nowadays, the search for effective molecules for chronic diseases treatments has increased. The cardiometabolic disorders still the main cause of death worldwide and plants may offer potential pharmacological innovative approaches to treat and prevent diseases. In the range of plant molecules are inserted the terpenes, which constituent essential elements with several pharmacological characteristics and applications, including cardiovascular and metabolic properties. Thus, the aim of the present review is to update the terpenes use on chronic disorders such as obesity, diabetes, hypertension and vascular conditions. The review includes a brief terpenes description based on the scientific literature in addition to data collected from secondary sources such as books and conference proceedings. We concluded that terpenes could act as adjuvant or main alternative treatment (when started earlier) to improve cardiometabolic diseases, contributing to reduce side effects of conventional drugs, in addition to preserving ethnopharmacological knowledge.

Terpenes with Antitumor Activity: A Patent Review.

BACKGROUND: Cancer is a major public health concern, and is one of the leading causes of death globally. Surgical removal, chemotherapy or hormonal therapy, radiation therapy, or a combination of them are treatment for cancer, many of which are ineffective or have serious side effects. In view of this, there is a search for new, more effective alternatives for cancer prevention and treatment. One possible source of compounds are natural products; among them, terpenes, a large class of organic compounds, have shown promise due to their anti-inflammatory, anti-tumorigenic, and hypolipidemic properties, among others recorded in the literature. OBJECTIVE: The study aims to use a patent review to evaluate the development and use of terpenes, or formulations containing terpenes, in new therapeutic options for the treatment of various types of cancer. METHODS: This patent review was carried out using the specialized patent databases of WIPO and Espacenet. The selection of patents was based on the following inclusion criteria which included pre-clinical and/or clinical trials, and demonstrated anti-tumor effects. RESULTS: Eight patents were identified, six from China, and two from Japan. In this review, all patents confirmed having good antitumor activity for many types of cancer cells. In addition, the inventors indicate more studies pre-clinical and clinical trials giving greater clarity and accurate reflection of the activity of the products studied. CONCLUSION: Natural products are an important source of compounds for use in the fight against cancer that can act synergistically, and help in the treatment of cancer.

Intestinal Anti-Inflammatory Activity of Terpenes in Experimental Models (2010-2020): A Review.

Inflammatory bowel diseases (IBDs) refer to a group of disorders characterized by inflammation in the mucosa of the gastrointestinal tract, which mainly comprises Crohn's disease (CD) and ulcerative colitis (UC). IBDs are characterized by inflammation of the intestinal mucosa, are highly debilitating, and are without a definitive cure. Their pathogenesis has not yet been fully elucidated; however, it is assumed that genetic, immunological, and environmental factors are involved. People affected by IBDs have relapses, and therapeutic regimens are not always able to keep symptoms in remission over the long term. Natural products emerge as an alternative for the development of new drugs; bioactive compounds are promising in the treatment of several disorders, among them those that affect the gastrointestinal tract, due to their wide structural diversity and biological activities. This review compiles 12 terpenes with intestinal anti-inflammatory activity evaluated in animal models and in vitro studies. The therapeutic approach to IBDs using terpenes acts basically to prevent oxidative stress, combat dysbiosis, restore intestinal permeability, and improve the inflammation process in different signaling pathways.

Anti-Estrogenic Activity of Guajadial Fraction, from Guava Leaves (Psidium guajava L.).

The research of natural products has allowed for the discovery of biologically relevant compounds inspired by plant secondary metabolites, which contributes to the development of many chemotherapeutic drugs used in cancer treatment. Psidium guajava leaves present a diverse phytochemical composition including flavonoids, phenolics, meroterpenoids, and triterpenes as the major bioactive constituents. Guajadial, a caryophyllene-based meroterpenoid, has been studied for potential anticancer effects tested in tumor cells and animal experimental models. Moreover, guajadial has been reported to have a mechanism of action similar to tamoxifen, suggesting this compound as a promisor phytoestrogen-based therapeutic agent. Herein, the anti-estrogenic action and anti-proliferative activity of guajadial is reported. The enriched guajadial fraction was obtained by sequential chromatographic techniques from the crude P. guajava dichloromethane extract showing promising anti-proliferative activity in vitro with selectivity for human breast cancer cell lines MCF-7 and MCF-7 BUS (Total Growth Inhibition = 5.59 and 2.27 µg·mL-1, respectively). Furthermore, evaluation of anti-estrogenic activity in vivo was performed demonstrating that guajadial enriched fraction inhibited the proliferative effect of estradiol on the uterus of pre-pubescent rats. These results suggest a relationship between anti-proliferative and anti-estrogenic activity of guajadial, which possibly acts in tumor inhibition through estrogen receptors due to the compounds structural similarity to tamoxifen.

Assessment of Anti-inflammatory and Antioxidant Properties of Safranal on CCI4-Induced Oxidative Stress and Inflammation in Rats.

The present study aimed to determine the antioxidative and anti-inflammatory effects of safranal on damage induced by CCl4. Experimental animals were divided into five groups. The first group was determined as the control group and no treatment was conducted. Second group rats were administered 1 mL/kg-day CCI4 during the experiment. Rats in Groups 3, 4 and 5 were administered 1 mL/kg-day CCI4 and 25 mg/kg, 50 mg/kg; 100 mg/kg safranal, respectively via gavage. Oxidative-antioxidant parameters, liver function enzymes and inflammatory cytokine levels were determined in liver samples obtained from the rats. Data analysis demonstrated that oxidative stress and inflammation markers were significantly higher in CCI4 administered groups (p<0.05). Antioxidant parameters in high-dose safranal administered groups were not different when compared to the control group. Safranal had ameliorating effects on the increased liver function enzymes activities in CCI4 administered groups. In conclusion, it was observed that CCI4 administration led to hepatic damage and increased oxidative stress and inflammatory cytokine levels. It was observed that particularly high-dose administration of safranal promoted the antioxidant system. Safranal administration was not effective on IL-1ß levels. However, high-dose (100 mg/kg) safranal was found to be inflammatory against TNF-α and IL-6 cytokines. In conclusion, it can be said that safranal has an anti-inflammatory potential and has a strong antioxidative effect.

Saponins from Quillaja saponaria and Quillaja brasiliensis: Particular Chemical Characteristics and Biological Activities.

Quillaja saponaria Molina represents the main source of saponins for industrial applications. Q. saponaria triterpenoids have been studied for more than four decades and their relevance is due to their biological activities, especially as a vaccine adjuvant and immunostimulant, which have led to important research in the field of vaccine development. These saponins, alone or incorporated into immunostimulating complexes (ISCOMs), are able to modulate immunity by increasing antigen uptake, stimulating cytotoxic T lymphocyte production (Th1) and cytokines (Th2) in response to different antigens. Furthermore, antiviral, antifungal, antibacterial, antiparasitic, and antitumor activities are also reported as important biological properties of Quillaja triterpenoids. Recently, other saponins from Q. brasiliensis (A. St.-Hill. & Tul.) Mart. were successfully tested and showed similar chemical and biological properties to those of Q. saponaria barks. The aim of this manuscript is to summarize the current advances in phytochemical and pharmacological knowledge of saponins from Quillaja plants, including the particular chemical characteristics of these triterpenoids. The potential applications of Quillaja saponins to stimulate further drug discovery research will be provided.

The use of terpenes and derivatives as a new perspective for cardiovascular disease treatment: a patent review (2008-2018).

INTRODUCTION: Terpenes are a class of secondary metabolites that can be found in a variety of animal and plants species. They are considered the most structurally diversified and abundant of all natural compounds. Several studies have shown the application of terpenes, such as carvacrol, linalool, and limonene in many pharmaceutical and medicinal fields, including cardiovascular disorders, the leading cause of death worldwide. AREAS COVERED: In this review, the authors outlined patents from the last 10 years relating to the therapeutic application of terpenes for the treatment and/or prevention of cardiovascular diseases found in different databases, emphasizing the possibility of these compounds becoming new drugs that may help to decrease the burden of these disorders. EXPERT OPINION: There has been a growing awareness over recent years of the therapeutic use of terpenes and their derivatives as new pharmaceutical products. Patents involving the use of terpenes have been especially important in the technological development of new strategies for the treatment of cardiovascular diseases by bringing new scientific knowledge into the pharmaceutical industry. Therefore, the development of biotechnologies using natural products should be encouraged in order to increase the variety of drugs available for the treatment of cardiovascular diseases.

In vitro and in vivo anti-Helicobacter pylori activity of Casearia sylvestris leaf derivatives.

ETHNOPHARMACOLOGICAL RELEVANCE: The number of bacterial strains that are resistant to multiple conventional antimicrobial agents is increasing. In this context, natural products have been widely used as a strategy to treat diseases caused by bacteria. Infections by Helicobacter pylori have attracted attention because they are directly related to severe gastric medical conditions. Casearia sylvestris Swartz, popularly known as guaçatonga, is largely employed to treat gastric disorders in Brazilian folk medicine. This plant species has aroused much interest mainly because it displays anti-inflammatory activity and can act as an antiulcer agent. AIM OF THE STUDY: To evaluate the in vitro and in vivo anti-H. pylori action of C. sylvestris leaf derivatives incorporated or not in a nanostructured drug delivery system. MATERIALS AND METHODS: The essential oil (obtained by hydrodistillation) and ethanolic extract (obtained by maceration) were obtained from C. sylvestris leaves. The ethanolic extract was submitted to fractionation through solid phase extraction and column chromatography, to yield the ethanolic fractions. Hydrolyzed casearin J was achieved by submitting isolated casearin J to acid hydrolysis. The derivatives were chemically characterized by nuclear magnetic resonance (NMR), gas chromatography (GC), and gas chromatography-mass spectrometry (GC-MS) analyses. A nanostructured lipid system was used as drug delivery system. To assess the in vitro antibacterial activity of C. sylvestris leaf essential oil, ethanolic extract, and derivatives, microdilution, biofilm, and time-kill assays were performed against H. pylori ATCC 43504. Finally, the in vivo action was investigated by employing male Wistar rats experimentally infected with H. pylori. RESULTS: Many C. sylvestris leaf derivatives presented significant in vitro activity against H. pylori. Among the derivatives, fraction 2 (F2) was the most effective. In vivo tests showed that both the ethanolic extract and F2 decreased the ulcerative lesion size, but only the ethanolic extract eradicated H. pylori from the gastric lesions. Incorporation of plant derivatives in nanostructured lipid system blunted the in vitro action, as demonstrated by the microdilution assay. However, this incorporation improved the ethanolic extract activity against biofilms. CONCLUSION: C. sylvestris leaf derivatives are effective against H. pylori both in vitro and in vivo. According to phytochemical analyses, these derivatives are rich in terpenoids, which could be related to the anti-H. pylori action. Synergism could also underlie C. sylvestris efficacy judging from the fact that the sub-fractions and isolated compounds had lower activity than the extract. Incorporation in a nanostructured lipid system did not improve the activity of the compounds in our in vivo protocol.

Efeito quimiopreventivo da Beta-ionona na hepatocarcinogênese associada à fibrose hepática / Chemopreventive effect of Beta-ionone in hepatocarcinogenesis associated with hepatic fibrosis

O carcinoma hepatocelular (HCC) é a neoplasia primária mais frequente que acomete o fígado, a quarta principal causa de morte relacionada ao câncer e apresenta mau prognóstico. A fibrose hepática está presente em grande parte dos casos de HCC e é um dos principais fatores de risco para esta afecção. Segundo estudos prévios do grupo, a ß-ionona (BI), presente em uvas e aromatizantes de vinho, apresenta potencial quimiopreventivo na hepatocarcinogênese principalmente por reduzir o número e tamanho de lesão pré neoplásica (LPN) e inibir a proliferação celular. No entanto, até o presente não foram identificados na literatura estudos que investigaram o efeito deste isoprenóide no processo fibrótico e na hepatocarcinogênese a ele associada. Desta forma, este estudo pretendeu investigar o potencial efeito quimiopreventivo da BI na hepatocarcinogênese associada à fibrose hepática. Para tanto, ratos machos Wistar foram tratados com óleo de milho (OM) [0,25 ml / 100 g de peso corporal (p.c.); Grupo de OM] ou BI (16mg / 100g p.c.; Grupo BI) durante 18 semanas. A partir da 2ª semana, todos os animais receberam uma dose intraperitoneal de dietilnitrosamina (DEN - 50 mg / Kg p.c.) uma vez por semana até a 16ª semana. Os animais foram eutanasiados em diferentes períodos do protocolo experimental: na 10a semana (grupos OMP1 e BIP1), na 14a semana (grupos OMP2 e BIP2) e na 18ª semana (grupos OMP3 e BIP3). O isoprenóide demonstrou, de maneira inédita na literatura, inibir o desenvolvimento da fibrose hepática em diferentes estágios da hepatocarcinogênese (pontos 1, 2 e 3) por reduzir (p < 0,05) a porcentagem de área marcada para picrosirius. Além disso, BI reduziu a porcentagem de área positiva para α- SMA (p < 0,05) e as concentrações de hidroxiprolina (p < 0,05) no ponto 2. Foi observada ação quimiopreventiva da BI nas fases iniciais da hepatocarcinogênese (pontos 1 e 2) mesmo em modelo associada a fibrose por reduzir (p < 0,05) o número e porcentagem de área do corte ocupada por LPN GSTP positivas. Este efeito não foi observado em fase mais avançada da hepatocarcinogênese (ponto 3). Corroborando este dado não foram observadas diferenças em relação ao número de tumores (p>=0,05) avaliados por imageamento e por análise histopatológica. No entanto, quando comparados ao seu controle (OMP3), os animais do grupo BIP3 apresentaram menor mortalidade e menor incidência (p < 0,05) de HCC high, considerado um tipo mais agressivo de HCC, sugerindo que este composto possa atuar na agressividade das células tumorais. O grupo BIP2 demonstrou ainda menor proliferação celular (p < 0,05) quando comparado ao grupo OMP2. Assim foram avaliadas as vias de proliferação celular PI3K/AKT e MAPK/ERK, bem como as proteínas p21 e p53, relacionadas a progressão do ciclo celular. Não foram observadas(p≥0,05) alterações nestas vias por parte do isoprenóide. O presente estudo demonstrou ação protetora da BI no desenvolvimento de fibrose, bem como na hepatocarcinogênese a ela associada. Contudo, são necessárias análises complementares para elucidar mecanismos pelos quais a BI atua na carcinigênese hepática associada à fibrose

Hepatocellular carcinoma (HCC) is the primary liver cancer, the fourth leading cause of death related to cancer and presents a poor prognosis. Hepatic fibrosis is present in most cases of HCC and represents one of the main risk factors for this condition. According to previous studies of the group, ß-ionone (BI), present in grapes and wine flavorings, has a potential chemopreventive in hepatocarcinogenesis mainly by reducing the number and size of preneoplastic lesions (LPN) and inhibiting cell proliferation. However, to date, no studies have been identified in the literature that investigated the effect of this isoprenoid on the fibrotic process and in its association with hepatocarcinogenesis. Thus, this study aimed to investigate the potential chemopreventive effect of BI in hepatocarcinogenesis associated with hepatic fibrosis. Male Wistar rats were treated with corn oil (OM) [0.25 ml / 100 g body weight (b.w.); OM] or BI group (16mg / 100g b.w; BI group) for 18 weeks. From week 2, all animals received an intraperitoneal dose of diethylnitrosamine (DEN - 50 mg / kg b.w.) once in a week until week 16. The animals were euthanized at different periods of the experimental protocol: at week 10 (groups OMP1 and BIP1), at week 14 (groups OMP2 and BIP2) and week 18 (groups OMP3 and BIP3). The isoprenoid, for the first time in the literature, shown to inhibit the development of liver fibrosis at different stages of hepatocarcinogenesis (points 1, 2 and 3) by reducing (p <0.05) the percentage of the area labeled for picrosirius. Also, BI reduced the percentage of α-SMA positive area (p <0.05) and hydroxyproline concentrations (p <0.05) at point 2. BI chemopreventive action was observed in the early stages of hepatocarcinogenesis (point 1 and 2) even in a model associated with fibrosis for reducing (p <0.05) the number and percentage of the liver section area occupied by GSTP positive LPN. This effect was not observed at a later stage of hepatocarcinogenesis (point 3). Corroborating this data, no differences were observed regarding the number of tumors (p>=0.05) evaluated by imaging and histopathological analysis. However, when compared to its control (OMP3), animals from the BIP3 group had lower mortality and lower incidence (p<0.05) of HCC high, considered a more aggressive type of HCC, suggesting that this compound may act in aggressiveness of tumor cells. The BIP2 group also showed lower cell proliferation (p <0.05) when compared to the OMP2 group. Thus, PI3K / AKT and MAPK / ERK cell proliferation pathways were evaluated, as well as p21 and p53 proteins, related to cell cycle progression. No changes were observed in these pathways by the isoprenoid (p≥0.05). The present study demonstrated the protective action of BI in the development of fibrosis, as well as its association with hepatocarcinogenesis. However, further analysis is needed to elucidate mechanisms by which BI acts on fibrosis-associated liver carcinogenesis

Effects of isopulegol in acute nociception in mice: Possible involvement of muscarinic receptors, opioid system and l-arginine/NO/cGMP pathway.

Previous studies have shown that isopulegol has anxiolytic, anticonvulsant, gastro-protective and antioxidant activities in rodents, but until now there are no studies showing activity of isopulegol in animal models of nociception and inflammation. The objective of this study was to evaluate the antinociceptive effect of isopulegol and to propose possible mechanisms involved in its effects observed in mice. Groups of male and female Swiss mice (20-35 g, n = 5-8) were used in this test under the authorization of Ethics Committee on Animal Experimentation (CEEA/UFPI N° 82/2014). In order to evaluate the antinociceptive activity of isopulegol, nociception was induced using formalin test, capsaicin and glutamate in hind paw licking model, followed by the investigation of the involvement of opioid mechanisms, K + ATP channels, muscarinic, L arginine-nitric oxide and cGMP. The oral administration of isopulegol showed antinociceptive effect in both phases of the formalin test at doses from 0.78 to 25 mg/kg (first phase) and 1.56-25 mg/kg (second phase) and also produced significant results before capsaicin test at doses from 1.56 to 12.5 mg/kg and glutamate test at doses from 3.12 to 6.25 mg/kg with a dose-dependent effect. The antinociception activity of isopulegol was inhibited in the presence of naloxone (2 mg / kg, ip), glibenclamide (3 mg/kg, ip), atropine (1 mg/kg, ip), l-arginine (600 mg/kg, ip) and methylene blue (20 mg/kg, ip). The results suggested that acute antinociceptive action of opioid isopulegol seems to be related to the K + ATP channels system, through the involvement of muscarinic receptors, inhibiting nitric oxide and cGMP.

Limonene: Aroma of innovation in health and disease.

Natural products obtained in dietary components may aid the prevention and treatment of a variety of diseases. Reports in the scientific literature have demonstrated that the consumption of terpenes is a successful alternative in the treatment of several diseases, triggering beneficial biological effects in clinical and preclinical studies. The monoterpene limonene is largely used in alimentary items, cleaning products, and it is one of the most frequent fragrances used in cosmetics formulation. The therapeutic effects of limonene have been extensively studied, proving anti-inflammatory, antioxidant, antinociceptive, anticancer, antidiabetic, antihyperalgesic, antiviral, and gastroprotective effects, among other beneficial effects in health. In this review, we collected, presented, and analyzed evidence from the scientific literature regarding the usage of limonene and its activities and underlying mechanisms involved in combating diseases. The highlighting of limonene applications could develop a useful targeting of innovative research in this field as well as the development of a limonene-based phytomedicine which could be used in a variety of conditions of health and disease.

Anticancer Properties of Essential Oils: An Overview.

BACKGROUND: Essential oils are complex mixtures of low molecular weight compounds extracted from plants. Their main constituents are terpenes and phenylpropanoids, which are responsible for their biological and pharmaceutical properties, such as insecticidal, parasiticidal, antimicrobial, antioxidant, anti-inflammatory, analgesic, antinociceptive, anticarcinogenic, and antitumor properties. Cancer is a complex genetic disease considered as a serious public health problem worldwide, accounting for more than 8 million deaths annually. OBJECTIVE: The activities of prevention and treatment of different types of cancer and the medicinal potential of essential oils are addressed in this review. CONCLUSION: Several studies have demonstrated anti-carcinogenic and antitumor activity for many essential oils obtained from various plant species. They may be used as a substitution to or in addition to conventional anti-cancer therapy. Although many studies report possible mechanisms of action for essential oils compounds, more studies are necessary in order to apply them safely and appropriately in cancer therapy.

D-limonene exhibits superior antihyperalgesic effects in a ß-cyclodextrin-complexed form in chronic musculoskeletal pain reducing Fos protein expression on spinal cord in mice.

Chronic musculoskeletal pain is one of the main symptoms found in Fibromyalgia with unclear etiology and limited pharmacological treatment. The aim of this study was to complex LIM in ß-cyclodextrin (LIM-ßCD) and then evaluate its antihyperalgesic effect in an animal model of chronic musculoskeletal pain. Differential scanning calorimetry and scanning electron microscopy was used for the characterization of the inclusion complex. Male Swiss mice were used for experimental procedures where mechanical hyperalgesia, thermal hyperalgesia, muscular strength, Fos immunofluorescence was studied after induction of hyperalgesia. Mechanism of action was also investigated through tail flick test and capsaicin-induced nociception. Endothermic events and morphological changes showed that the slurry complex method was the best method for the complexation. After induction of hyperalgesia, the oral administration of LIM-ßCD (50mg/kg) significantly increased the paw withdrawal threshold compared to uncomplexed limonene. Fos immunofluorescence showed that both compounds significantly decreased the number of Fos-positive cells in the dorsal horn. In nociceptive tests, FLU was able to reverse the antinociceptive effect of LIM-ßCD. After intraplantar administration of capsaicin, LIM was able to significantly decrease time to lick. LIM-ßCD has antihyperalgesic action superior to its uncomplexed form, with possible action in the dorsal horn of the spinal cord. These results suggest the possible applicability of LIM, uncomplexed or complexed with ßCD, in conditions such as FM and neuropathic pain, for which there are currently only limited pharmacological options.

Geraniol Induces Antinociceptive Effect in Mice Evaluated in Behavioural and Electrophysiological Models.

Geraniol (GER) is a monoterpene alcohol with various biochemical and pharmacological properties present in the essential oil of more than 160 species of herbs (especially the Cymbopogon genus). In this study, we evaluated the antinociceptive activity of GER in behavioural and electrophysiological in vitro experimental models of nociception using male Swiss mice. GER (12.5, 25 or 50 mg/kg i.p. and 50 or 200 mg/kg p.o.) reduced the number of writhes induced by acetic acid. The opioid antagonist naloxone (5 mg/kg s.c.) administered in mice subsequently treated with GER (25 mg/kg i.p.) did not reverse such antinociceptive activity, suggesting a non-opioid pathway for the mechanism of action. GER (12.5, 25 and 50 mg/kg i.p.) reduced paw licking time in the second phase of the formalin test. Also, in the glutamate test, GER when administered 50 mg/kg i.p. reduced paw licking time, probably modulating glutamatergic neurotransmission. GER blocked reversibly components of the compound action potential (CAP) recorded in isolated sciatic nerve in a concentration- and drug exposure time-dependent manner: 1 mM to 120 min. for the first component and 0.6 mM to 90 min. for the second component. The IC50 was calculated for the peak-to-peak amplitude (PPA) at 0.48 ± 0.04 mM. The conduction velocity was also reduced by exposure to GER starting from the concentration of 0.3 mM for both components of the CAP. In conclusion, it is suggested that GER has antinociceptive activity, especially in pain related to inflammation, and in part related to reduced peripheral nerve excitability.

Effect of Lemongrass Aroma on Experimental Anxiety in Humans.

OBJECTIVES: The objective of this study was to evaluate the potential anxiolytic effect of lemongrass (Cymbopogon citratus) aroma in healthy volunteers submitted to an anxiogenic situation. DESIGN: Forty male volunteers were allocated to four different groups for the inhalation of lemongrass essential oil (test aroma: three or six drops), tea tree essential oil (control aroma: three drops), or distilled water (nonaromatic control: three drops). Immediately after inhalation, each volunteer was submitted to an experimental model of anxiety, the video-monitored version of the Stroop Color-Word Test (SCWT). OUTCOME MEASURES: Psychologic parameters (state anxiety, subjective tension, tranquilization, and sedation) and physiologic parameters (heart rate and gastrocnemius electromyogram activity) were evaluated before the inhalation period and before, during, and after the SCWT. RESULTS: Individuals exposed to the test aroma (three and six drops), unlike the control groups, presented a reduction in state anxiety and subjective tension, immediately after treatment administration. In addition, although they presented an anxious response to the task, they completely recovered from it in 5 min, unlike the control groups. Physiologic alterations along the test were not prevented by any treatment, in the same way as has previously been observed for diazepam. CONCLUSIONS: Although more investigations are necessary to clarify the clinical relevance of lemongrass essential oil as an anxiety treatment, this work shows that very brief exposure to this aroma has some perceived anxiolytic effects.

Seco-taondiol, an unusual meroterpenoid from the Chilean seaweed Stypopodium flabelliforme and its gastroprotective effect in mouse model.

Ten known meroterpenoids and the new meroterpenoid 7 were isolated from the Chilean seaweed Stypopodium flabelliforme as their acetylated derivatives. Furthermore, the known metabolite taondiol has been isolated for the first time from this species. The molecular structure of the new metabolite was determined by spectroscopic methods based on 1D- and 2D-NMR. Isolation of 7 represents a key step toward a better understanding of the biogenesis of this class of meroterpenoids. Among the meroditerpenoids isolated, stypodiol, isoepitaondiol, epitaondiol and sargaol exhibited gastroprotective activity on the HCl/Ethanol-induced gastric lesions model in mice. Regarding the mode of gastroprotective action, the activity of epitaondiol was reversed significantly when animals were pretreated with indomethacin, N-ethylmaleimide and N-nitro-l-arginine methyl ester (L-NAME) suggesting that prostaglandins, sulfhydryl groups and nitric oxide are involved in their mode of gastroprotective action. In the case of sargaol the gastroprotective activity was attenuated with indomethacin and N-ethylmaleimide, which suggests that prostaglandins and sulfhydryl groups are also involved in the mode of action using this model.