RESUMEN
A series of novel quinoline-based tetracyclic ring-systems were synthesized and evaluated in vitro for their antiplasmodial, antiproliferative and antimicrobial activities. The novel hydroiodide salts 10 and 21 showed the most promising antiplasmodial inhibition, with compound 10 displaying higher selectivity than the employed standards. The antiproliferative assay revealed novel pyridophenanthridine 4b to be significantly more active against human prostate cancer (IC50 = 24 nM) than Puromycin (IC50 = 270 nM) and Doxorubicin (IC50 = 830 nM), which are used for clinical treatment. Pyridocarbazoles 9 was also moderately effective against all the employed cancer cell lines and moreover showed excellent biofilm inhibition (9a: MBIC = 100 µM; 9b: MBIC = 100 µM).
Asunto(s)
Alcaloides Indólicos/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Antiinfecciosos/farmacología , Antimaláricos/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Alcaloides Indólicos/metabolismo , Plasmodium falciparum/efectos de los fármacos , Quinolinas/metabolismo , Relación Estructura-ActividadRESUMEN
Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.
Asunto(s)
Lisina Acetiltransferasa 5/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Metabolismo Energético , Humanos , MasculinoRESUMEN
Androgen receptor (AR) stimulators, such as androgen and Tip60, play a pivotal role in prostatic carcinogenesis as androgen receptor signaling is critical for the growth and transformation of the prostate gland. Moreover, androgen and Tip60 promotes HIF-1α activation, involved in metabolic reprogramming by increasing glycolysis, a hallmark in cancer initiation and development. In this study we evaluated the effect of androgen and Tip60 stimulus in AR pathway activation and HIF-1α stabilization, in terms of proliferation and cell metabolism in androgen-sensitive LNCaP cells. The protective role of the bioactive compounds sulforaphane and capsaicin against the effect of these stimuli leading to pro-carcinogenic features was also addressed. Sulforaphane and capsaicin decreased nuclear AR, prostate specific antigen and Bcl-XL levels, and cell proliferation induced by androgen and Tip60 in LNCaP cells. These bioactive compounds prevented the increase in glycolysis, hexokinase and pyruvate kinase activity, and reduced HIF-1α stabilization induced by androgen and Tip60 in LNCaP cells. The protective role of sulforaphane and capsaicin on prostate cancer may rely on mechanisms involving the inhibition of Tip60, AR and HIF-1α effects.
Asunto(s)
Andrógenos/metabolismo , Capsaicina/farmacología , Isotiocianatos/farmacología , Lisina Acetiltransferasa 5/metabolismo , Receptores Androgénicos/efectos de los fármacos , Receptores Androgénicos/metabolismo , Capsaicina/química , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Glucólisis , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isotiocianatos/química , Lisina Acetiltransferasa 5/genética , Masculino , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/metabolismo , Piruvato Quinasa/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfóxidos , Proteína bcl-X/metabolismoRESUMEN
Triheptanoin, the triglyceride of heptanoate, is anaplerotic (refills deficient tricarboxylic acid cycle intermediates) via the propionyl-CoA carboxylase pathway. It has been shown to be neuroprotective and anticonvulsant in several models of neurological disorders. Here, we investigated the effects of triheptanoin against changes of hippocampal mitochondrial functions, oxidative stress and cell death induced by pilocarpine-induced status epilepticus (SE) in mice. Ten days of triheptanoin pre-treatment did not protect against SE, but it preserved hippocampal mitochondrial functions including state 2, state 3 ADP, state 3 uncoupled respiration, respiration linked to ATP synthesis along with the activities of pyruvate dehydrogenase complex and oxoglutarate dehydrogenase complex 24 h post-SE. Triheptanoin prevented the SE-induced reductions of hippocampal mitochondrial superoxide dismutase activity and plasma antioxidant status as well as lipid peroxidation. It also reduced neuronal degeneration in hippocampal CA1 and CA3 regions 3 days after SE. In addition, heptanoate significantly reduced hydrogen peroxide-induced cell death in cultured neurons. In situ hybridization localized the enzymes of the propionyl-CoA carboxylase pathway, specifically Pccα, Pccß and methylmalonyl-CoA mutase to adult mouse hippocampal pyramidal neurons and dentate granule cells, indicating that anaplerosis may occur in neurons. In conclusion, triheptanoin appears to have anaplerotic and antioxidant effects which contribute to its neuroprotective properties.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Hipocampo/metabolismo , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/prevención & control , Degeneración Nerviosa/prevención & control , Estrés Oxidativo/efectos de los fármacos , Estado Epiléptico/tratamiento farmacológico , Estado Epiléptico/patología , Triglicéridos/uso terapéutico , Animales , Región CA1 Hipocampal/metabolismo , Región CA3 Hipocampal/metabolismo , Ciclo del Ácido Cítrico/efectos de los fármacos , Convulsivantes , Masculino , Ratones , Pilocarpina , Estado Epiléptico/inducido químicamenteRESUMEN
This review summarises the recent findings on metabolic treatments for epilepsy and Amyotrophic Lateral Sclerosis (ALS) in honour of Professor Ursula Sonnewald. The metabolic impairments in rodent models of these disorders as well as affected patients are being discussed. In both epilepsy and ALS, there are defects in glucose uptake and reduced tricarboxylic acid (TCA) cycling, at least in part due to reduced amounts of C4 TCA cycle intermediates. In addition there are impairments in glycolysis in ALS. A reduction in glucose uptake can be addressed by providing the brain with alternative fuels, such as ketones or medium-chain triglycerides. As anaplerotic fuels, such as the triglyceride of heptanoate, triheptanoin, refill the TCA cycle C4/C5 intermediate pool that is deficient, they are ideal to boost TCA cycling and thus the oxidative metabolism of all fuels.
Asunto(s)
Esclerosis Amiotrófica Lateral/dietoterapia , Esclerosis Amiotrófica Lateral/metabolismo , Encéfalo/metabolismo , Epilepsia/dietoterapia , Epilepsia/metabolismo , Animales , Dieta Cetogénica/métodos , Ácidos Grasos/administración & dosificación , Ácidos Grasos/metabolismo , Glucólisis/fisiología , Humanos , Triglicéridos/administración & dosificación , Triglicéridos/metabolismoRESUMEN
The nuclear factor erythroid 2-related factor 2 pathway (Nrf2) has been previously identified to protect the brain against various impacts. Here, we investigated the effect of the Nrf2 activator sulforaphane in various seizure models and hippocampal mitochondrial bioenergetics. We found that daily injections of sulforaphane for 5 days elevated the seizure thresholds to 6 Hz stimulation and fluorothyl-, but not pentylenetetrazole-induced tonic seizures and protected mice against pilocarpine-induced status epilepticus (SE). Also, sulforaphane increased the antioxidant defences within hippocampal formations and blood plasma. In addition, sulforaphane treatment reduced the extent of hippocampal lipid peroxidation 24 h post-SE and protected hippocampal mitochondria against SE-induced reduction in state 2 and uncoupler-stimulated state 3 respiration. SE-mediated partial loss of rotenone-sensitive and complex II-driven respiration was reduced, consistent with the enhanced activities of complexes I and II in sulforaphane-treated SE mice. In mitochondria isolated from both no SE and SE mice, sulforaphane increased state 3 respiration and respiration linked to ATP synthesis, which may contribute to its anticonvulsant and antioxidant effects by providing more ATP for cellular vital and protective functions. However, sulforaphane did not prevent SE-induced hippocampal cell death. In conclusion, sulforaphane and/or Nrf2 activation are viable anticonvulsant strategies, which are antioxidant and enhance mitochondrial function, especially the ability to produce ATP. Sulforaphane was anticonvulsant in two acute mouse models of epilepsy and protected mice against pilocarpine-induced status epilepticus (SE). We also found antioxidant effects of sulforaphane in mouse plasma and hippocampal formations, exhibited by increased catalase and superoxide dismutase (SOD) activity, as well as increased abilities of hippocampal mitochondria to produce ATP. These effects likely underlie sulforaphane's anticonvulsant mechanisms of action.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , Epilepsia/patología , Hipocampo/ultraestructura , Isotiocianatos/uso terapéutico , Mitocondrias/efectos de los fármacos , Animales , Convulsivantes/toxicidad , Modelos Animales de Enfermedad , Complejo I de Transporte de Electrón/metabolismo , Electrochoque/efectos adversos , Epilepsia/etiología , Flurotilo/toxicidad , Hipocampo/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Ratones , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/prevención & control , Estrés Oxidativo/efectos de los fármacos , Pentilenotetrazol/toxicidad , Pilocarpina/toxicidad , Sulfóxidos , Superóxido Dismutasa/metabolismoRESUMEN
Triheptanoin, the triglyceride of heptanoate, is anticonvulsant in various epilepsy models. It is thought to improve energy metabolism in the epileptic brain by re-filling the tricarboxylic acid (TCA) cycle with C4-intermediates (anaplerosis). Here, we injected mice with [1,2-(13) C]glucose 3.5-4 weeks after pilocarpine-induced status epilepticus (SE) fed either a control or triheptanoin diet. Amounts of metabolites and incorporations of (13) C were determined in extracts of cerebral cortices and hippocampal formation and enzyme activity and mRNA expression were quantified. The percentage enrichment with two (13) C atoms in malate, citrate, succinate, and GABA was reduced in hippocampal formation of control-fed SE compared with control mice. Except for succinate, these reductions were not found in triheptanoin-fed SE mice, indicating that triheptanoin prevented a decrease of TCA cycle capacity. Compared to those on control diet, triheptanoin-fed SE mice showed few changes in most other metabolite levels and their (13) C labeling. Reduced pyruvate carboxylase mRNA and enzyme activity in forebrains and decreased [2,3-(13) C]aspartate amounts in cortex suggest a pyruvate carboxylation independent source of C-4 TCA cycle intermediates. Most likely anaplerosis was kept unchanged by carboxylation of propionyl-CoA derived from heptanoate. Further studies are proposed to fully understand triheptanoin's effects on neuroglial metabolism and interaction.
Asunto(s)
Ciclo del Ácido Cítrico/fisiología , Modelos Animales de Enfermedad , Epilepsia/metabolismo , Pilocarpina/toxicidad , Triglicéridos/administración & dosificación , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Ciclo del Ácido Cítrico/efectos de los fármacos , Epilepsia/inducido químicamente , Epilepsia/tratamiento farmacológico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Ratones , Distribución AleatoriaRESUMEN
Meat consumption plays a critical role in the development of several types of cancer. Hemin, a metabolite of myoglobin produced after meat intake, has been demonstrated to be involved in the cancer initiation phase. Macrophages are key components of the innate immunity, which, upon activation, can prevent cancer development by eliminating neoplastic cells. Metabolic reprogramming, characterized by high glycolysis and low oxidative phosphorylation, is critical for macrophage activation. 3,4-dihydroxyphenylacetic acid (3,4DHPAA) and 4-hydroxyphenylacetic acid (4HPAA), both microbiota-derived metabolites of flavonoids, have not been extensively studied although they exert antioxidant properties. The aim of this study was to determine the effect of hemin on the anticancer properties of macrophages and the role of 3,4DHPAA and 4HPAA in metabolic reprogramming and activation of macrophages leading to the elimination of cancer cells. The results showed that hemin inhibited glycolysis, glycolytic, and pentose phosphate pathway (PPP) enzyme activities and hypoxia-inducible factor-1 alpha (HIF-1α) stabilization, which interferes with macrophage activation (evidenced by decreased interferon-γ-inducible protein 10 (IP-10) release) and their ability to eliminate cancer cells (via cytotoxic mediators and phagocytosis). Hemin also reduced the mitochondrial membrane potential (MMP) and mitochondrial mass in macrophages. 3,4DHPAA and 4HPAA, by stimulating glycolysis and PPP, prevented the impairment of the macrophage anticancer activity induced by hemin. In conclusion, 3,4HPAA and 4HPAA administration could represent a promising strategy for preventing the reduction of macrophage activation induced by hemin.
RESUMEN
Triheptanoin, the medium-chain triglyceride of heptanoate, has been shown to be anticonvulsant and neuroprotective in several neurological disorders. In the gastrointestinal tract, triheptanoin is cleaved to heptanoate, which is then taken up by the blood and most tissues, including liver, heart and brain. Here we evaluated the neuroprotective effects of heptanoate and its effects on mitochondrial oxygen consumption in vitro. We also investigated the neuroprotective effects of triheptanoin compared to long-chain triglycerides when administered after stroke onset in rats. Heptanoate pre-treatment protected cultured neurons against cell death induced by oxygen glucose deprivation and N-methyl-D-aspartate. Incubation of cultured astrocytes with heptanoate for 2 h increased mitochondrial proton leak and also enhanced basal respiration and ATP turnover, suggesting that heptanoate protects against oxidative stress and is used as fuel. However, continuous 72 h infusion of triheptanoin initiated 1 h after middle cerebral artery occlusion in rats did not alter stroke volume at 3 days or neurological deficit at 1 and 3 days relative to long-chain triglyceride control treatment.
Asunto(s)
Heptanoatos/uso terapéutico , Infarto de la Arteria Cerebral Media/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Triglicéridos/uso terapéutico , Animales , Células Cultivadas , Heptanoatos/metabolismo , Heptanoatos/farmacología , Infarto de la Arteria Cerebral Media/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuroprotección/efectos de los fármacos , Neuroprotección/fisiología , Fármacos Neuroprotectores/farmacología , Ratas , Ratas Wistar , Resultado del Tratamiento , Triglicéridos/farmacologíaRESUMEN
Cholesterol plays an important role in inducing pancreatic ß-cell dysfunction, leading to an impaired insulin secretory response to glucose. This study aimed to determine the protective effects of sulforaphane, a natural isothiocyanate Nrf2-inducer, against cholesterol-induced pancreatic ß-cells dysfunction, through molecular and cellular mechanisms involving mitochondrial bioenergetics. Sulforaphane prevented cholesterol-induced alterations in the coupling efficiency of mitochondrial respiration, improving ATP turnover and spare capacity, and averted the impairment of the electron flow at complexes I, II, and IV. Sulforaphane also attenuated the cholesterol-induced activation of the NFκB pathway, normalizing the expression of pro- and anti-inflammatory cytokines. In addition, it also inhibited the decrease in sirtuin 1 expression and greatly increased Pgc-1α expression in Min6 cells. Sulforaphane increased the expression of antioxidant enzymes downstream of the Nrf2 pathway and prevented lipid peroxidation induced by cholesterol. The antioxidant and anti-inflammatory properties of sulforaphane and its ability to protect and improve mitochondrial bioenergetic function contribute to its protective action against cholesterol-induced pancreatic ß-cell dysfunction. Our data provide a scientifically tested foundation upon which sulforaphane can be developed as nutraceutical to preserve ß-cell function and eventually control hyperglycemia.
Asunto(s)
Colesterol/toxicidad , Metabolismo Energético/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Isotiocianatos/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Células Cultivadas , Suplementos Dietéticos , Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Inflamación , Células Secretoras de Insulina/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , SulfóxidosRESUMEN
The hypothesis that chronic feeding of the triglycerides of octanoate (trioctanoin) and decanoate (tridecanoin) in "a regular non-ketogenic diet" is anticonvulsant was tested and possible mechanisms of actions were subsequently investigated. Chronic feeding of 35E% of calories from tridecanoin, but not trioctanoin, was reproducibly anticonvulsant in two acute CD1 mouse seizure models. The levels of beta-hydroxybutyrate in plasma and brain were not significantly increased by either treatment relative to control diet. The respective decanoate and octanoate levels are 76 µM and 33 µM in plasma and 1.17 and 2.88 nmol/g in brain. Tridecanoin treatment did not alter the maximal activities of several glycolytic enzymes, suggesting that there is no reduction in glycolysis contributing to anticonvulsant effects. In cultured astrocytes, 200 µM of octanoic and decanoic acids increased basal respiration and ATP turnover, suggesting that both medium chain fatty acids are used as fuel. Only decanoic acid increased mitochondrial proton leak which may reduce oxidative stress. In mitochondria isolated from hippocampal formations, tridecanoin increased respiration linked to ATP synthesis, indicating that mitochondrial metabolic functions are improved. In addition, tridecanoin increased the plasma antioxidant capacity and hippocampal mRNA levels of heme oxygenase 1, and FoxO1.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Antioxidantes/uso terapéutico , Encéfalo/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Convulsiones/tratamiento farmacológico , Triglicéridos/uso terapéutico , Ácido 3-Hidroxibutírico/sangre , Animales , Anticonvulsivantes/administración & dosificación , Antioxidantes/administración & dosificación , Glucemia/análisis , Encéfalo/enzimología , Encéfalo/metabolismo , Decanoatos/sangre , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos , Mitocondrias/metabolismo , Convulsiones/sangre , Convulsiones/metabolismo , Triglicéridos/administración & dosificaciónRESUMEN
Studying rats fed high cholesterol diet and a pancreatic ß-cell line (Min6), we aimed to determine the mechanisms by which quercetin protects against cholesterol-induced pancreatic ß-cell dysfunction and impairments in glycemic control. Quercetin prevented the increase in total plasma cholesterol, but only partially prevented the high cholesterol diet-induced alterations in lipid profile. Quercetin prevented cholesterol-induced decreases in pancreatic ATP levels and mitochondrial bioenergetic dysfunction in Min6 cells, including decreases in mitochondrial membrane potentials and coupling efficiency in the mitochondrial respiration (basal and maximal oxygen consumption rate (OCR), ATP-linked OCR and reserve capacity). Quercetin protected against cholesterol-induced apoptosis of Min6 cells by inhibiting caspase-3 and -9 activation and cytochrome c release. Quercetin prevented the cholesterol-induced decrease in antioxidant defence enzymes from pancreas (cytosolic and mitochondrial homogenates) and Min6 cells and the cholesterol-induced increase of cellular and mitochondrial oxidative status and lipid peroxidation. Quercetin counteracted the cholesterol-induced activation of the NFκB pathway in the pancreas and Min6 cells, normalizing the expression of pro-inflammatory cytokines. Quercetin inhibited the cholesterol-induced decrease in sirtuin 1 expression in the pancreas and pancreatic ß-cells. Taken together, the anti-apoptotic, antioxidant and anti-inflammatory properties of quercetin, and its ability to protect and improve mitochondrial bioenergetic function are likely to contribute to its protective action against cholesterol-induced pancreatic ß-cell dysfunction, thereby preserving glucose-stimulated insulin secretion (GSIS) and glycemic control. Specifically, the improvement of ATP-linked OCR and the reserve capacity are important mechanisms for protection of quercetin. In addition, the inhibition of the NFκB pathway is an important mechanism for the protection of quercetin against cytokine mediated cholesterol-induced glycemic control impairment. In summary, our data highlight cellular, molecular and bioenergetic mechanisms underlying quercetin's protective effects on ß-cells in vitro and in vivo, and provide a scientifically tested foundation upon which quercetin can be developed as a nutraceutical to preserve ß-cell function.
Asunto(s)
Colesterol/metabolismo , Inflamación/metabolismo , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Biogénesis de Organelos , Quercetina/farmacología , Animales , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Glucemia , Línea Celular , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Insulina/sangre , Insulina/metabolismo , Masculino , FN-kappa B/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , RatasRESUMEN
Medium chain triglycerides (MCTs) are used to treat neurologic disorders with metabolic impairments, including childhood epilepsy and early Alzheimer's disease. However, the metabolic effects of MCTs in the brain are still unclear. Here, we studied the effects of feeding even and uneven MCTs on brain glucose metabolism in the mouse. Adult mice were fed 35% (calories) of trioctanoin or triheptanoin (the triglycerides of octanoate or heptanoate, respectively) or a matching control diet for 3 weeks. Enzymatic assays and targeted metabolomics by liquid chromatography tandem mass spectrometry were used to quantify metabolites in extracts from the hippocampal formations (HFs). Both oils increased the levels of ß-hydroxybutyrate, but no other significant metabolic alterations were observed after triheptanoin feeding. The levels of glucose 6-phosphate and fructose 6-phosphate were increased in the HF of mice fed trioctanoin, whereas levels of metabolites further downstream in the glycolytic pathway and the pentose phosphate pathway were reduced. This indicates that trioctanoin reduces glucose utilization because of a decrease in phosphofructokinase activity. Trioctanoin and triheptanoin showed similar anticonvulsant effects in the 6 Hz seizure model, but it remains unknown to what extent the anticonvulsant mechanism(s) are shared. In conclusion, triheptanoin unlike trioctanoin appears to not alter glucose metabolism in the healthy brain.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Caprilatos/administración & dosificación , Glucosa/metabolismo , Hipocampo/metabolismo , Convulsiones/prevención & control , Triglicéridos/administración & dosificación , Animales , Anticonvulsivantes/química , Caprilatos/química , Ciclo del Ácido Cítrico/efectos de los fármacos , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Convulsiones/dietoterapia , Convulsiones/metabolismo , Relación Estructura-Actividad , Triglicéridos/químicaRESUMEN
Luteolin, a common plant polyphenolic flavonoid, has antioxidant, neuroprotective, anxiolytic and anti-inflammatory properties, which led us to hypothesize that luteolin is anticonvulsant. Here, we evaluated the effects of acute and chronic luteolin injection (i.p.) in four mouse seizure models, the 6 Hz model, maximal electroshock test (MEST), pentylenetetrazole (PTZ) and second hit PTZ test in the chronic stage of the pilocarpine model. Using real-time PCR mRNA levels of toll like receptor 4 (Tlr4), were quantified in the pilocarpine model, because luteolin has been shown to block the downstream signaling of TLR4. Luteolin did not exhibit any consistent anti- or pro-convulsant actions after single dosing in the 6 Hz (0.3-10 mg/kg), MEST (0.3-20 mg/kg) and PTZ (3 mg/kg) tests, nor after repeated daily dosing (10 mg/kg) in the 6 Hz model. Tlr4 mRNA levels were upregulated 3 days after pilocarpine-induced status epilepticus (SE), but unaltered at three weeks in the chronic stage of the model. At that time, there was no effect of repeated luteolin injections (10 mg/kg, i.p.) in the second hit PTZ test, indicating that TLR-4 signaling may be not one of the main players determining the seizure threshold in this seizure model. In summary, we found no indications that luteolin is pro- or anti-convulsant in one chronic and three acute mouse seizure models.