RESUMO
The study aimed to examine the effect of intraperitoneal and intrathecal (±)-licarin A in neuropathic pain induced by L5 and L6 spinal nerve ligation (SNL) in male Wistar rats and the possible involvement of the NO-cGMP-ATP-sensitive K+ channel pathway. Neuropathic pain signs (allodynia and hyperalgesia) were evaluated on postoperative Day 14 using von Frey filaments. Single intraperitoneal (0.01, 0.1, 1, and 10 mg/kg) and intrathecal (0.01, 0.1, 1, and 10 µg/rat) administration of (±)-licarin A improved allodynia and hyperalgesia. The (±)-licarin A-induced anti-allodynic and anti-hyperalgesic activity was prevented by the intrathecal injection of l-NAME (100 µg/rat; nonselective nitric oxide synthase inhibitor), ODQ (10 µg/rat; guanylate cyclase inhibitor), and glibenclamide (50 µg/rat; adenosine triphosphate (ATP)-sensitive K+ channel blocker). The data suggest that (±)-licarin A exerts its anti-allodynic and anti-hyperalgesic activity by activating the NO-cGMP-ATP-sensitive K+ channel pathway.
Assuntos
Hiperalgesia , Lignanas , Neuralgia , Ratos , Masculino , Animais , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , GMP Cíclico/metabolismo , Ratos Wistar , Trifosfato de Adenosina , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Óxido Nítrico/metabolismoRESUMO
Natural metabolites present an extraordinary chemo-diversity and have been used as the inspiration for new drugs. Considering the need for new treatments against the neglected parasitic disease leishmaniasis, three semi-synthetic derivatives of natural neolignane licarin A were prepared: O-acetyl (1a), O-allyl (1b), and 5-allyl (1c). Using an ex vivo assay, compounds 1a, 1b, and 1c showed activity against the intracellular amastigotes of Leishmania (L.) infantum, with IC50 values of 9, 13, and 10 µM, respectively. Despite no induction of hemolytic activity, only compound 1b resulted in mammalian cytotoxicity (CC50 = 64 µM). The most potent compounds (1a and 1c) resulted in selectivity indexes >18. The mechanism of action of compound 1c was evaluated by fluorescent/luminescent based techniques and MALDI-TOF/MS. After a short incubation period, increased levels of the cytosolic calcium were observed in the parasites, with alkalinization of the acidocalcisomes. Compound 1c also induced mitochondrial hyperpolarization, resulting in decreased levels of ATP without altering the reactive oxygen species (ROS). Neither plasma membrane damages nor DNA fragmentation were observed after the treatment, but a reduction in the cellular proliferation was detected. Using MALDI-TOF/MS, mass spectral alterations of promastigote proteins were observed when compared to untreated and miltefosine-treated groups. This chemically modified neolignan induced lethal alterations of the bioenergetic and protein metabolism of Leishmania. Future PKPD and animal efficacy studies are needed to optimize this promising natural-derived compound.
Assuntos
Antiprotozoários , Leishmania infantum , Animais , Camundongos , Antiprotozoários/farmacologia , Cálcio/metabolismo , Leishmania infantum/metabolismo , Metabolismo Energético , Camundongos Endogâmicos BALB C , Mamíferos/metabolismoRESUMO
Dehydrodiisoeugenol (DHIE) is a neolignan found in more than 17 plant species, including herbs, fruit, and root. DHIE was, for the first time, isolated from Myristica fragrans bark in 1973. Since then, many methodologies have been used for the obtention of DHIE, including classical chemistry synthesis using metal catalysts and biocatalytic synthesis; employing horseradish peroxidase; peroxidase from Cocos nucifera; laccase; culture cells of plants; and microorganisms. Increasing evidence has indicated that DHIE has a wide range of biological activities: anti-inflammatory, anti-oxidant, anti-cancerogenic, and anti-microbial properties. However, evidence in vivo and in human beings is still lacking to support the usefulness potential of DHIE as a therapeutic agent. This study's review was created by searching for relevant DHIE material on websites such as Google Scholar, PubMed, SciFinder, Scholar, Science Direct, and others. This reviews the current state of knowledge regarding the different synthetical routes and biological applications of DHIE.
RESUMO
Schistosomiasis mansoni is an infectious parasitic disease caused by worms of the genus Schistosoma, and praziquantel (PZQ) is the medication available for the treatment of schistosomiasis. However, the existence of resistant strains reinforces the need to develop new schistosomicidal drugs safely and effectively. Thus, the (±)-licarin A neolignan incorporated into poly-Æ-caprolactone (PCL) nanoparticles and not incorporated were evaluated for their in vivo schistosomicidal activity. The (±)-licarin A -loaded poly(ε-caprolactone) nanoparticles and the pure (±)-licarin A showed a reduction in the number of worm eggs present in spleens of mice infected with Schistosoma mansoni. In addition, the (±)-licarin A incorporated in the concentration of 20 mg/kg and 200 mg/kg reduced the number of worms, presenting percentages of 56.3% and 41.7%, respectively.
Assuntos
Nanopartículas , Esquistossomose mansoni , Esquistossomicidas , Animais , Caproatos , Lactonas , Lignanas , Camundongos , Poliésteres , Schistosoma mansoni , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/parasitologia , Esquistossomicidas/farmacologia , Esquistossomicidas/uso terapêuticoRESUMO
Schistosomiasis is a widespread human parasitic disease currently affecting over 200 million people, particularly in poor communities. Chemotherapy for schistosomiasis relies exclusively on praziquantel (PZQ). Previous studies have shown that licarin A (LIC-A), a dihydrobenzofuran neolignan, exhibited in vitro antiparasitic activity against Schistosoma mansoni adult worms. This study aimed to investigate the potential of LIC-A, isolated as main metabolite from leaves of Nectandra oppositifolia Nees & Mart. (Lauraceae), as an antischistosomal agent orally active in schistosomiasis animal model. PZQ was used as a reference compound. As result, LIC-A showed, at a single dose of 400 mg/kg, to be able to partially cure infected mice (worm burden reductions of ~50%). Parasite eggs, that are responsible for a variety of pathologies and transmission of schistosomiasis, were also moderately inhibited by LIC-A (egg burden reductions of ~50%-60%). Furthermore, it was observed that LIC-A achieved a slight reduction of hepatomegaly and splenomegaly. Collectively, although LIC-A was partially active when administered orally, these results give support for the antiparasitic potential LIC-A as lead compound for novel antischistosomal agent.
Assuntos
Lauraceae , Lignanas , Esquistossomose mansoni , Animais , Lauraceae/química , Lignanas/farmacologia , Camundongos , Contagem de Ovos de Parasitas , Schistosoma mansoni , Esquistossomose mansoni/tratamento farmacológicoRESUMO
Purpose: This study investigated the safety and therapeutic efficacy of licarin A (LCA) in the treatment of intraocular inflammation. Methods:In vitro safety of LCA in retinal pigmented epithelial cells (ARPE-19) and human embryonic stem cell derived-retinal pigmented epithelial cells (hES-RPE) was evaluated using CellTiter-Blue® kit. The chorioallantoic membrane (CAM) assay was used to investigate LCA safety and antiangiogenic activity. In vivo safety of intravitreal LCA was accomplished by clinical examination (including assessment of intraocular pressure), electroretinography (ERG), and histopathology. Uveitis was induced in rats by subcutaneous and intravitreal injection of bacillus Calmette-Guérin (BCG) antigen of Mycobacterium bovis. Intraocular inflammation was graded by slit-lamp and fundus examination, ERG, and histopathology. Results: LCA was safe to cells and to the CAM at concentration below 12.0 µM. LCA significantly reduced the percentage of blood vessels in the CAM. Retinal safety and anti-inflammatory efficacy of intravitreal injection of LCA 6.0 µM were confirmed through clinical, functional, and histopathological evaluation. Significant reduction of inflammatory cytokines (tumor necrosis factor-α and interleukin-6) was also found, when compared to untreated animals. Conclusion: The results suggest that LCA is a potential new drug for the treatment of inflammatory eye disease.
Assuntos
Inibidores da Angiogênese/farmacologia , Inflamação/tratamento farmacológico , Lignanas/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Membrana Corioalantoide/metabolismo , Modelos Animais de Doenças , Descoberta de Drogas , Eletrorretinografia/métodos , Oftalmopatias/patologia , Inflamação/diagnóstico , Pressão Intraocular/efeitos dos fármacos , Injeções Intravítreas , Lignanas/administração & dosagem , Lignanas/uso terapêutico , Masculino , Ratos , Ratos Wistar , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/embriologia , Segurança , Resultado do Tratamento , Uveíte/induzido quimicamente , Uveíte/patologiaRESUMO
Several species of rapidly growing mycobacteria (RGM) have been associated with biofilms in areas such as biomedical devices, water distribution systems, cosmetic surgery, and catheter-related blood infections. Biofilms which exhibit antimicrobial resistance such as those formed by the genus Mycobacterium pose a significant risk to health and are of particular interest to researchers. Licarin A (a neolignan found in numerous plant species e.g. nutmeg) has been reported to show a wide range of biological actions including anti-inflammatory, antioxidant, and antibacterial properties. The aim of this study was to prepare a set of Licarin A derivatives and investigate the impact of specific structural changes on its antimycobacterial ability, and its effect on the biofilm formation of RGM species. Initially, the phenolic sub-unit and alkenyl side chain of Licarin A were modified to create derivatives with a higher partition coefficient; as the activity of a compound against mycobacteria seems to be strongly influenced by its hydrophobicity. Further, polar groups were inserted into the side chain to change the hydrophilic-lipophilic profile of the molecules. Results showed variability in the susceptibility profile of mycobacteria against the Licarin A derivatives under analysis. A number of the derivatives showed significant inhibitory activity of planktonic growth of the three strains of mycobacteria used, with even lower MIC values than those observed with reference drugs and Licarin A itself. Cytotoxicity assays showed they also have low toxicity, confirming that structural modifications to the Licarin A have made improvements to its antimycobacterial properties.
Assuntos
Biofilmes/efeitos dos fármacos , Lignanas/química , Lignanas/farmacologia , Mycobacterium/efeitos dos fármacos , Micobactérias não Tuberculosas/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Claritromicina/farmacologia , Testes de Sensibilidade Microbiana , Myristica/química , Micobactérias não Tuberculosas/fisiologia , Sulfametoxazol/farmacologiaRESUMO
This paper reports the synthesis of (±)-licarin A 1, a dihydrobenzofuran neolignan, resultant of an oxidative coupling reaction of isoeugenol and horseradish peroxidase (HRP) enzyme. Following, three semi-synthetic derivatives from this compound were obtained: benzylated (±)-licarin A 2, methylated (±)-licarin A 3 and acetylated (±)-licarin A 4. After structural elucidation and assignment by Nuclear Magnetic Resonance of 1H, 13C and DEPT, all compounds were evaluated in vitro against Trypomastigote forms of Trypanosoma cruzi (T. cruzi), the etiologic agent of Chagas disease, and Schistosoma mansoni (S. mansoni) worms, the etiologic agent of schistosomiasis. Compound (4) was the most active against S. mansoni adult worms, displaying worm viability reduction at 25 µM and mortality of all worms at 100 and 200 µM within 24 h. Compound 1 was the second most active, showing worm viability reduction at 50 µM and mortality of 25% and 100% of worms in 24h at concentrations of 100 and 200 µM, respectively. In addition, theoretical calculations aiming at finding molecular properties that showed the correlation for schistosomicidal and trypanocidal activities of (±)-licarin A and three of its semi-synthetic derivatives were also performed.
Assuntos
Lignanas/síntese química , Schistosoma mansoni/efeitos dos fármacos , Esquistossomicidas/síntese química , Tripanossomicidas/síntese química , Trypanosoma cruzi/efeitos dos fármacos , Animais , Doença de Chagas/tratamento farmacológico , Simulação por Computador , Lignanas/farmacologia , Lignanas/uso terapêutico , Esquistossomose/tratamento farmacológico , Esquistossomicidas/farmacologia , Tripanossomicidas/farmacologiaRESUMO
Leishmaniasis' treatment is based mostly on pentavalent antimonials or amphotericin B long-term administration, expensive drugs associated with severe side effects. Considering these aforementioned, the search for alternative effective and safe leishmaniasis treatments is a necessity. This work evaluated a neolignan, licarin A anti-leishmanial activity chemically synthesized by our study group. It was observed that licarin A effectively inhibited Leishmania (Leishmania) major promastigotes (IC50 of 9.59 ± 0.94 µg/mL) growth, by inducing in these parasites genomic DNA fragmentation in a typical death pattern by apoptosis. Additionally, the neolignan proved to be even more active against intracellular amastigotes of the parasite (EC50 of 4.71 ± 0.29 µg/mL), and significantly more effective than meglumine antimoniate (EC50 of 216.2 ± 76.7 µg/mL) used as reference drug. The antiamastigote activity is associated with an immunomodulatory activity, since treatment with licarin A of the infected macrophages induced a decrease in the interleukin (IL)-6 and IL-10 production. This study demonstrates for the first time the antileishmanial activity of licarin A and suggests that the compound may be a promising in the development of a new leishmanicidal agent.