RESUMEN
Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.
Asunto(s)
Endocannabinoides/metabolismo , Nocicepción/efectos de los fármacos , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Receptor Cannabinoide CB1/agonistas , Animales , Técnica del Anticuerpo Fluorescente , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/patología , Ganglios Espinales/fisiopatología , Masculino , Ratones , Oxaliplatino/antagonistas & inhibidores , Dimensión del Dolor , Enfermedades del Sistema Nervioso Periférico/metabolismo , Receptor Cannabinoide CB1/metabolismo , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
The number of people with dementia worldwide is estimated at 50 million by 2018 and continues to rise mainly due to increasing aging and population growth. Clinical impact of current interventions remains modest and all efforts aimed at the identification of new therapeutic approaches are therefore critical. Previously, we showed that JM-20, a dihydropyridine-benzodiazepine hybrid molecule, protected memory processes against scopolamine-induced cholinergic dysfunction. In order to gain further insight into the therapeutic potential of JM-20 on cognitive decline and Alzheimer's disease (AD) pathology, here we evaluated its neuroprotective effects after chronic aluminum chloride (AlCl3) administration to rats and assessed possible alterations in several types of episodic memory and associated pathological mechanisms. Oral administration of aluminum to rodents recapitulates several neuropathological alterations and cognitive impairment, being considered a convenient tool for testing the efficacy of new therapies for dementia. We used behavioral tasks to test spatial, emotional- associative and novel object recognition memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study revealed that JM-20 prevented memory decline alongside the inhibition of AlCl3 -induced oxidative stress, increased AChE activity, TNF-α and pro-apoptotic proteins (like Bax, caspase-3, and 8) levels. JM-20 also protected against neuronal damage in the hippocampus and prefrontal cortex. Our findings expanded our understanding of the ability of JM-20 to preserve memory in rats under neurotoxic conditions and confirm its potential capacity to counteract cognitive impairment and etiological factors of AD by breaking the progression of key steps associated with neurodegeneration.
Asunto(s)
Cloruro de Aluminio/toxicidad , Benzodiazepinas/farmacología , Trastornos de la Memoria/inducido químicamente , Memoria/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Niacina/análogos & derivados , Cloruro de Aluminio/antagonistas & inhibidores , Animales , Hipocampo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Mitocondrias/efectos de los fármacos , Prueba del Laberinto Acuático de Morris/efectos de los fármacos , Niacina/farmacología , Prueba de Campo Abierto/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Wistar , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
AIMS: The present study was designed to investigate whether the antinociceptive effect of bone marrow-derived mesenchymal stem/stromal cells (MSC) during oxaliplatin (OXL)-induced sensory neuropathy is related to antioxidant properties. MAIN METHODS: Male mice C57BL/6 were submitted to repeated intravenous administration of OXL (1 mg/kg, 9 administrations). After the establishment of sensory neuropathy, mice were treated with a single intravenous administration of MSC (1 × 106), vehicle or gabapentin. Paw mechanical and thermal nociceptive thresholds were evaluated through von Frey filaments and cold plate test, respectively. Motor performance was evaluated in the rota-rod test. Gene expression profile, cytokine levels, and oxidative stress markers in the spinal cord were evaluated by real-time PCR, ELISA and biochemical assays, respectively. KEY FINDINGS: OXL-treated mice presented behavioral signs of sensory neuropathy, such as mechanical allodynia and thermal hyperalgesia, which were completely reverted by a single administration of MSC. Repeated oral treatment with gabapentin (70 mg/kg) induced only transient antinociception. The IL-1ß and TNF-α spinal levels did not differ between mice with or without sensory neuropathy. MSC increased the levels of anti-inflammatory cytokines, IL-10 and TGF-ß, in the spinal cord of neuropathic mice, in addition to increasing the gene expression of antioxidant factors SOD and Nrf-2. Additionally, nitrite and MDA spinal levels were reduced by the MSC treatment. SIGNIFICANCE: MSC induce reversion of sensory neuropathy induced by OXL possibly by activation of anti-inflammatory and antioxidant pathways, leading to reestablishment of redox homeostasis in the spinal cord.
Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Oxaliplatino/toxicidad , Oxidación-Reducción , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Células Receptoras Sensoriales/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Animales , Interleucina-1beta/metabolismo , Masculino , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/fisiología , Ratones , Ratones Endogámicos C57BL , Nocicepción , Oxidación-Reducción/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/terapia , Reacción en Cadena en Tiempo Real de la Polimerasa , Prueba de Desempeño de Rotación con Aceleración Constante , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/fisiología , Médula Espinal/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Cassava (Manihot esculenta Crantz) is a plant that contains neurotoxins such as linamarin and lotaustraline. Its long-term consumption is associated with neuronal damage and contributes to the development of motor impairment in humans and rats. We investigated the effects of the consumption of cassava juice on renal and hepatic function and motor impairments in male rats. The rats received the vehicle, non-toxic and toxic doses of cassava juice, or linamarin as a pharmacological control, over 35 consecutive days. The effects were evaluated in an open field test, rotarod, and swim test. The toxic cassava dose and linamarin resulted in motor impairments in the rotarod and swim test from day 7 of treatment. The toxic cassava dose and linamarin increased the parameters that indicate renal and hepatic damage, with the exception of total protein and albumin levels. Behavioral variables that show motor incoordination (i.e., latency to fall in the rotarod) were negatively correlated with biochemical parameters of renal and kidney damage, whereas spin behavior was positively correlated. Our data indicate that chronic oral consumption of cassava juice caused renal and hepatic damage that was correlated with motor coordination impairment in rats, similarly to their principal neurotoxic compound, linamarin.
Asunto(s)
Jugos de Frutas y Vegetales/toxicidad , Manihot , Animales , Riñón/metabolismo , Hígado/metabolismo , Masculino , Actividad Motora , Ratas Wistar , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Motor behavior alterations are a shared hallmark of neurodegenerative diseases affecting motor circuits, such as amyotrophic lateral sclerosis (ALS), Parkinson's, and Huntington's diseases. In patients and transgenic animal models of amyotrophic lateral sclerosis fine movements controlled by distal muscles are the first to be affected, but its study and knowledge remain poorly understood, mainly because most of the tests used for describing the motor alterations are focused on the function of proximal muscles and gross movements. In this study we demonstrate that alterations of phalangeal fine movements can be quantitatively evaluated using a novel procedure designed by us, phalangeal tension recording test, which showed high sensitivity to detect such alterations. The evaluation was carried out during the motor neuron (MN) degenerative process induced by the acute and chronic overactivation of AMPA receptors in the lumbar rat spinal cord, using previously described models. The new method allowed the quantification of significant alterations of the fine movements of the hindpaws phalanges when AMPA was infused in the lumbar segment controlling the distal muscles, but not when a more rostral spinal segment was infused, and these alterations were not detected by the rotarod or the stride tests. These changes occurred before the paralysis of the hindlimbs. Studying the early distal motor alterations before the total paralysis at late stages is essential for understanding the initial consequences of MN degeneration and therefore for designing new strategies for the control, treatment and prevention of MN diseases.
Asunto(s)
Neuronas Motoras/patología , Movimiento/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/administración & dosificación , Animales , Modelos Animales de Enfermedad , Fuerza de la Mano , Masculino , Ratas Wistar , Receptores AMPA/agonistas , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative condition that affects the Central Nervous System (CNS). Insect venoms show high molecular variability and selectivity in the CNS of mammals and present potential for the development of new drugs for the treatment of PD. In this study, we isolated and identified a component of the venom of the social wasp Parachartergus fraternus and evaluated its neuroprotective activity in the murine model of PD. For this purpose, the venom was filtered and separated through HPLC; fractions were analyzed through mass spectrometry and the active fraction was identified as a novel peptide, called Fraternine. We performed two behavioral tests to evaluate motor discoordination, as well as an apomorphine-induced rotation test. We also conducted an immunohistochemical assay to assess protection in TH+ neurons in the Substantia Nigra (SN) region. Group treated with 10 µg/animal of Fraternine remained longer in the rotarod compared to the lesioned group. In the apomorphine test, Fraternine decreased the number of rotations between treatments. This dose also inhibited dopaminergic neuronal loss, as indicated by immunohistochemical analysis. This study identified a novel peptide able to prevent the death of dopaminergic neurons of the SN and recover motor deficit in a 6-OHDA-induced murine model of PD.
Asunto(s)
Conducta Animal/efectos de los fármacos , Neuronas Dopaminérgicas/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Péptidos/farmacología , Sustancia Negra/efectos de los fármacos , Venenos de Avispas/química , Animales , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Femenino , Masculino , Ratones , Degeneración Nerviosa , Fármacos Neuroprotectores/aislamiento & purificación , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/fisiopatología , Péptidos/aislamiento & purificación , Prueba de Desempeño de Rotación con Aceleración Constante , Sustancia Negra/metabolismo , Sustancia Negra/fisiopatología , AvispasRESUMEN
Dysferlinopathies are muscle dystrophies caused by mutations in the gene encoding dysferlin, a relevant protein for membrane repair and trafficking. These diseases are untreatable, possibly due to the poor knowledge of relevant molecular targets. Previously, we have shown that human myofibers from patient biopsies as well as myotubes derived from immortalized human myoblasts carrying a mutated form of dysferlin express connexin proteins, but their relevance in myoblasts fate and function remained unknown. In the present work, we found that numerous myoblasts bearing a mutated dysferlin when induced to acquire myogenic commitment express PPARγ, revealing adipogenic instead of myogenic commitment. These cell cultures presented many mononucleated cells with fat accumulation and within 48 h of differentiation formed fewer multinucleated cells. In contrast, dysferlin deficient myoblasts treated with boldine, a connexin hemichannels blocker, neither expressed PPARγ, nor accumulated fat and formed similar amount of multinucleated cells as wild type precursor cells. We recently demonstrated that myofibers of skeletal muscles from blAJ mice (an animal model of dysferlinopathies) express three connexins (Cx39, Cx43, and Cx45) that form functional hemichannels (HCs) in the sarcolemma. In symptomatic blAJ mice, we now show that eight-week treatment with a daily dose of boldine showed a progressive recovery of motor activity reaching normality. At the end of this treatment, skeletal muscles were comparable to those of wild type mice and presented normal CK activity in serum. Myofibers of boldine-treated blAJ mice also showed strong dysferlin-like immunoreactivity. These findings reveal that muscle dysfunction results from a pathophysiologic mechanism triggered by mutated dysferlin and downstream connexin hemichannels expressed de novo lead to a drastic reduction of myogenesis and favor muscle damage. Thus, boldine could represent a therapeutic opportunity to treat dysfernilopathies.
Asunto(s)
Aporfinas/farmacología , Conexinas/metabolismo , Disferlina/genética , Músculo Esquelético/patología , Mioblastos/patología , Animales , Diferenciación Celular/efectos de los fármacos , Disferlina/deficiencia , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inmunología , Distrofia Muscular de Cinturas/patología , Mioblastos/efectos de los fármacos , Fármacos Neuromusculares Despolarizantes/farmacología , Prueba de Desempeño de Rotación con Aceleración Constante , Sarcolema/efectos de los fármacosRESUMEN
Dysferlinopathy is a genetic human disease caused by mutations in the gene that encodes the dysferlin protein (DYSF). Dysferlin is believed to play a relevant role in cell membrane repair. However, in dysferlin-deficient (blAJ) mice (a model of dysferlinopathies) the recovery of the membrane resealing function by means of the expression of a mini-dysferlin does not arrest progressive muscular damage, suggesting the participation of other unknown pathogenic mechanisms. Here, we show that proteins called connexins 39, 43 and 45 (Cx39, Cx43 and Cx45, respectively) are expressed by blAJ myofibers and form functional hemichannels (Cx HCs) in the sarcolemma. At rest, Cx HCs increased the sarcolemma permeability to small molecules and the intracellular Ca2+ signal. In addition, skeletal muscles of blAJ mice showed lipid accumulation and lack of dysferlin immunoreactivity. As sign of extensive damage and atrophy, muscles of blAJ mice presented elevated numbers of myofibers with internal nuclei, increased number of myofibers with reduced cross-sectional area and elevated creatine kinase activity in serum. In agreement with the extense muscle damage, mice also showed significantly low motor performance. We generated blAJ mice with myofibers deficient in Cx43 and Cx45 expression and found that all above muscle and systemic alterations were absent, indicating that these two Cxs play a critical role in a novel pathogenic mechanism of dysfernolophaties, which is discussed herein. Therefore, Cx HCs could constitute an attractive target for pharmacologic treatment of dyferlinopathies.
Asunto(s)
Conexina 43/genética , Conexinas/genética , Disferlina/genética , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/prevención & control , Miofibrillas/genética , Animales , Calcio/metabolismo , Conexina 43/deficiencia , Conexinas/deficiencia , Creatina Quinasa/sangre , Creatina Quinasa/genética , Modelos Animales de Enfermedad , Disferlina/deficiencia , Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , Mutación , Miofibrillas/metabolismo , Miofibrillas/patología , Permeabilidad , Condicionamiento Físico Animal , Prueba de Desempeño de Rotación con Aceleración Constante , Sarcolema/metabolismoRESUMEN
This work describes the neuropharmacological (sedative, anxiolytic, antidepressant, and anticonvulsant) actions of Gardenin A (GA) (0.1-25 mg/kg p.o.), a flavonoid found in medicinal plants. The sedative effects of GA were assessed with the pentobarbital-induced sleep test. The anxiolytic actions of GA were evaluated with the elevated plus-maze, the light-dark box test, the exploratory cylinder assay, and the open field test. Motor coordination was evaluated with the rotarod test and the open field test. The antidepressant-like actions of GA were evaluated with the tail suspension test and forced swimming test. The mechanisms of the anxiolytic-like and antidepressant-like effects of GA were assessed using inhibitors of neurotransmission pathways. The anticonvulsant activity of GA was evaluated with the strychnine-induced seizure test. The sedative effects of GA were evident only at a dose of 25 mg/kg, which increased the duration of sleep but did not alter sleep onset. GA showed anxiolytic-like actions with activity comparable to that of clonazepam in all experimental tests. The GABAA receptor antagonist bicuculline reversed the anxiolytic-like effects of GA. Furthermore, GA showed significant antidepressant-like actions in both models with activity comparable to that of fluoxetine. Yohimbine, an α2-adrenoceptor blocker, inhibited the antidepressant-like actions of GA. In addition, GA (1-10 mg/kg) did not affect locomotor coordination in mice and delayed the onset of convulsions. These findings suggest that GA induces anxiolytic-like effects and has anticonvulsant actions by the possible involvement of the GABAergic system. The antidepressant-like actions of GA may be mediated by noradrenergic neurotransmission.
Asunto(s)
Ansiolíticos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Antidepresivos/uso terapéutico , Flavonas/uso terapéutico , Hipnóticos y Sedantes/uso terapéutico , Convulsiones/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Prueba de Desempeño de Rotación con Aceleración Constante , Convulsiones/inducido químicamente , Estricnina , NataciónRESUMEN
Chronic pain management has several adverse effects and research looking for new and effective pain management drugs posing lower undesirable effects is necessary. Given the above, the pharmacological investigation of medicinal plants significantly contributes to the dissemination of plant-derived therapeutics. The aim of this study was to evaluate the antinociceptive activity of the Psidium brownianum Mart ex DC. leaf essential oil (PBEO) and the participation of the opioid pathway in this effect in mice. Swiss Mus musculus male mice were tested using acute nociception models (acetic acid induced abdominal contortions, formalin, capsaicin and hot plate tests). The possible myorelaxant action of the PBEO was tested using the rotarod test. The essential oil reduced animal nociception in chemical and heat models, with this action being devoid of a myorelaxant effect. Naloxone (2 mg/kg, intraperitoneally - i.p.) partially antagonized the PBEO activity, possibly acting via opioid receptors. The results obtained provide evidence that the traditional Psidium brownianum use may be effective for pain treatment.
Asunto(s)
Analgésicos/farmacología , Aceites Volátiles/farmacología , Extractos Vegetales/farmacología , Hojas de la Planta/química , Psidium/química , Animales , Modelos Animales de Enfermedad , Dosificación Letal Mediana , Masculino , Ratones , Nocicepción/efectos de los fármacos , Dolor/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Trauma to the peripheral nervous system (PNS) results in loss of motor and sensory functions. After an injury, a complex series of events begins, allowing axonal regeneration and target reinnervation. However, this regenerative potential is limited by several factors such as age, distance from the lesion site to the target and severity of lesion. Many studies look for ways to overcome these limitations. Inosine, a purine nucleoside derived from adenosine, emerges as a potential treatment, due to its capacity to regulate axonal growth, neuroprotection and immunomodulation, contributing to motor recovery. However, no studies demonstrated their effects on PNS. C57/Black6 mice were submitted to sciatic nerve crush and received intraperitoneal injections of saline or inosine (70â¯mg/kg), one hour after injury and daily for one week. To evaluate axonal regeneration and functional recovery, electroneuromyography, Sciatic Function Index (SFI), rotarod and pinprick tests were performed. Our results showed that the inosine group presented a higher number of myelinated fibers and a large amount of fibers within the ideal G-ratio. In addition, the results of electroneuromyography showed greater amplitude of the compound muscle action potentials in the first and second weeks, suggesting anticipation of regeneration in the inosine group. We also observed in the inosine group, motor and sensory neurons survival, reduction in the number of macrophages and myelin ovoids in the sciatic nerves, and an early recovery of motor and sensory functions. Thus, we conclude that the use of inosine accelerates axonal regeneration promoting an early recovery of motor and sensory functions.
Asunto(s)
Inosina/farmacología , Compresión Nerviosa , Regeneración Nerviosa/efectos de los fármacos , Traumatismos de los Nervios Periféricos/prevención & control , Nervio Ciático/efectos de los fármacos , Animales , Electromiografía , Inyecciones Intraperitoneales , Inosina/administración & dosificación , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Regeneración Nerviosa/fisiología , Fármacos Neuroprotectores/farmacología , Traumatismos de los Nervios Periféricos/patología , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante , Nervio Ciático/lesionesRESUMEN
BACKGROUND: The development of new therapeutic strategies to treat amyotrophic lateral sclerosis (ALS) is of utmost importance. The use of cyclic nitroxides such as tempol may provide neuroprotection and improve lifespan. We investigated whether tempol (50 mg/kg) presents therapeutic potential in SOD1G93A transgenic mice. METHODS: Tempol treatment began at the asymptomatic phase of the disease (10th week) and was administered every other day until week 14, after which it was administered twice a week until the final stage of the disease. The animals were sacrificed at week 14 (initial stage of symptoms-ISS) and at the end stage (ES) of the disease. The lumbar spinal cord of the animals was dissected and processed for use in the following techniques: Nissl staining to evaluate neuronal survival; immunohistochemistry to evaluate astrogliosis and microgliosis (ISS and ES); qRT-PCR to evaluate the expression of neurotrophic factors and pro-inflammatory cytokines (ISS); and transmission electron microscopy to evaluate the alpha-motoneurons (ES). Behavioral analyses considering the survival of animals, bodyweight loss, and Rotarod motor performance test started on week 10 and were performed every 3 days until the end-stage of the disease. RESULTS: The results revealed that treatment with tempol promoted greater neuronal survival (23%) at ISS compared to untreated animals, which was maintained until ES. The intense reactivity of astrocytes and microglia observed in vehicle animals was reduced in the lumbar spinal cords of the animals treated with tempol. In addition, the groups treated with tempol showed reduced expression of proinflammatory cytokines (IL1ß and TNFα) and a three-fold decrease in the expression of TGFß1 at ISS compared with the group treated with vehicle. CONCLUSIONS: Altogether, our results indicate that treatment with tempol has beneficial effects, delaying the onset of the disease by enhancing neuronal survival and decreasing glial cell reactivity during ALS progression in SOD1G93A mice.
Asunto(s)
Esclerosis Amiotrófica Lateral/fisiopatología , Óxidos N-Cíclicos/uso terapéutico , Inflamación/tratamiento farmacológico , Destreza Motora/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Médula Espinal/efectos de los fármacos , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Supervivencia Celular/efectos de los fármacos , Óxidos N-Cíclicos/farmacología , Modelos Animales de Enfermedad , Femenino , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/metabolismo , Masculino , Ratones , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Destreza Motora/fisiología , Fármacos Neuroprotectores/farmacología , Prueba de Desempeño de Rotación con Aceleración Constante , Marcadores de Spin , Médula Espinal/metabolismo , Médula Espinal/patología , Superóxido Dismutasa-1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Background and Purpose- Inhibition of brain NKCC1 (Na+-K+-Cl- cotransporter 1) with bumetanide (BMT) is of interest in ischemic stroke therapy. However, its poor brain penetration limits the application. In this study, we investigated the efficacy of 2 novel NKCC1 inhibitors, a lipophilic BMT prodrug STS5 (2-(Dimethylamino)ethyl 3-(butylamino)-4-phenoxy-5-sulfamoyl-benzoate;hydrochloride) and a novel NKCC1 inhibitor STS66 (3-(Butylamino)-2-phenoxy-5-[(2,2,2-trifluoroethylamino)methyl]benzenesulfonamide), on reducing ischemic brain injury. Methods- Large-vessel transient ischemic stroke in normotensive C57BL/6J mice was induced with 50-min occlusion of the middle cerebral artery and reperfusion. Focal, permanent ischemic stroke in angiotensin II (Ang II)-induced hypertensive C57BL/6J mice was induced by permanent occlusion of distal branches of middle cerebral artery. A total of 206 mice were randomly assigned to receive vehicle DMSO, BMT, STS5, or STS66. Results- Poststroke BMT, STS5, or STS66 treatment significantly decreased infarct volume and cerebral swelling by ≈40% to 50% in normotensive mice after transient middle cerebral artery occlusion, but STS66-treated mice displayed better survival and sensorimotor functional recovery. STS5 treatment increased the mortality. Ang II-induced hypertensive mice exhibited increased phosphorylatory activation of SPAK (Ste20-related proline alanine-rich kinase) and NKCC1, as well as worsened infarct and neurological deficit after permanent distal middle cerebral artery occlusion. Conclusions- The novel NKCC1 inhibitor STS66 is superior to BMT and STS5 in reducing ischemic infarction, swelling, and neurological deficits in large-vessel transient ischemic stroke, as well as in permanent focal ischemic stroke with hypertension comorbidity.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Encéfalo/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/uso terapéutico , Miembro 2 de la Familia de Transportadores de Soluto 12 , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Encéfalo/patología , Isquemia Encefálica/patología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Prueba de Desempeño de Rotación con Aceleración Constante , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/farmacología , Accidente Cerebrovascular/patología , Resultado del TratamientoRESUMEN
AIMS: To explore the antidepressant- and anxiolytic-like effects of an aqueous extract of Turnera diffusa Willd (Turneraceae) and to explore its possible toxic side effects on behavior, target organ function, and spermatic quality. MATERIALS AND METHODS: Acute effects of a T. diffusa aqueous extract were evaluated in adult male mice with the plus-maze, forced swimming and open field tests to identify the possible anxiolytic, antidepressant and stimulant effects of this extract. Effects of T. diffusa aqueous extract were further investigated through two approaches. a) Male and female adult mice receiving a 28-day treatment were evaluated in a neurobehavioral test battery; later, changes in their biochemical parameters and in target organ morphology were analyzed. b) In young adult (16-weeks old) and mature (46-weeks old) males, spermatic quality and testes morphology during a complete spermatogenesis cycle were analyzed after a 35-day treatment. RESULTS: T. diffusa aqueous extract induced remarkable anxiolytic- and antidepressant-like effects without affecting locomotor activity. This extract did not elicit behavioral signs of neural side effects, a sex-dependent reduction in body weight gain was produced without affecting functional parameters or the morphology of target organs. The highest dose improved cellular turnover in the testes of mature mice. CONCLUSION: T. diffusa aqueous extract induced a clear anxiolytic-like effect, and for the first time, we reported an antidepressant effect. Clinical potential or even intake of T. diffusa in the context of traditional medicine can be supported by its efficacy to positively modulate behavior and its safety for a wide range of doses.
Asunto(s)
Ansiolíticos/farmacología , Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Extractos Vegetales/farmacología , Turnera/química , Animales , Ansiolíticos/aislamiento & purificación , Ansiolíticos/toxicidad , Antidepresivos/aislamiento & purificación , Antidepresivos/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Especificidad de Órganos , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Prueba de Desempeño de Rotación con Aceleración Constante , Espermatogénesis/efectos de los fármacos , Natación , Testículo/efectos de los fármacos , Testículo/patologíaRESUMEN
Agathisflavone (AGF) is a biflavonoid with a number of important biological and pharmacological activities, such as antioxidant, antimicrobial, and neuroprotective effects. However, its toxicological effects have not been fully investigated. Accordingly, the aim of this study was to investigate the toxicological effects of AGF in mice. For this purpose, the median lethal dose 50% (LD50) was determined along with the anatomic and histopathological parameters (weight, alimentation, excretion, biochemical, and hematological) in fertile untouched female Swiss mice. Results suggest that during the treatment, no deaths were reported at 300 and 2000 mg/kg (n = 03/group, p.o.). Moreover, AGF did not cause significant change in the above mentioned parameters in test animals when compared with the control group (0.05% Tween 80 dissolved in 0.9% saline). Taken all together, this non-clinical toxicological study revealed that AGF has an LD50 larger than 2000 mg/kg and did not change significantly the hematological, biochemical, histopathological, behavioral, as well as physiological parameters in the female mice.
Asunto(s)
Biflavonoides/toxicidad , Extractos Vegetales/toxicidad , Animales , Biflavonoides/aislamiento & purificación , Evaluación Preclínica de Medicamentos/métodos , Femenino , Dosificación Letal Mediana , Ratones , Extractos Vegetales/aislamiento & purificación , Hojas de la Planta , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante/métodosRESUMEN
Salvia tiliifolia Vahl (Lamiaceae) is used for the empirical treatment of pain and inflammation. The diterpenoid tilifodiolide (TFD) was isolated from Salvia tiliifolia. The in vitro anti-inflammatory effects of TFD (0.1-200 µM) were assessed using murine macrophages stimulated with LPS and estimating the levels of pro-inflammatory mediators for 48 h. The in vivo anti-inflammatory activity of TFD was assessed using the carrageenan-induced paw edema test for 6 h. The antinociceptive effects of TFD were evaluated using the formalin test and the acetic acid induced-writhing test. The effects of TFD on locomotor activity were assessed using the open field test and the rotarod test. TFD inhibited the production of TNF-α (IC50 = 5.66 µM) and IL-6 (IC50 = 1.21 µM) in macrophages. TFD (200 mg/kg) showed anti-inflammatory effects with similar activity compared to 10 mg/kg indomethacin. The administration of TFD induced antinociception in the phase 1 (ED50 = 48.2 mg/kg) and the phase 2 (ED50 = 28.9 mg/kg) of the formalin test. In the acetic acid assay, TFD showed antinociceptive effects (ED50 = 32.3 mg/kg) with similar potency compared to naproxen (ED50 = 36.2 mg/kg). In the presence of different inhibitors in the acetic acid assay, only the co-administration of TFD and naloxone reverted the antinociceptive activity shown by TFD alone. TFD did not affect locomotor activity in mice. TFD exerts in vitro and in vivo anti-inflammatory activity and in vivo antinociceptive effects.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios/farmacología , Diterpenos/farmacología , Dimensión del Dolor/efectos de los fármacos , Salvia/química , Animales , Diterpenos/química , Diterpenos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Indometacina/farmacología , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Actividad Motora , Naloxona/farmacología , Naproxeno/farmacología , Prueba de Desempeño de Rotación con Aceleración Constante , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Here in, we report the preparation and evaluation of four 3-hydroxy-piperidine-N-benzyl-aryl-acylhydrazone derivatives (6a-d) for their potential antinociceptive activity. In the tail flick test, compounds 6a and 6d exhibited a significant increase in the latency time of the animals, in comparison to the control group. These two compounds also showed a significant increase in the nociceptive threshold from 1 to 6â¯h after treatment in the CCI neuropathic pain model. In both cases, the antinociceptive activity was blocked by naloxone, suggesting an opioid mechanism of action, but without sedative or motor coordination effects.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Hidrazonas/uso terapéutico , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Umbral del Dolor , Temperatura , Analgésicos Opioides/farmacología , Animales , Formaldehído , Hidrazonas/síntesis química , Hidrazonas/química , Hidrazonas/farmacología , Masculino , Ratones , Umbral del Dolor/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Antianxiety drugs currently in use are associated with a number of serious side effects. Present study was designed to evaluate the efficacy of anacardic acids (AAs) isolated from cashew nut (Anacardium occidentale L.) shell liquid (CNSL) to treat anxiety as well as its role in oxidative stress in mice model. Anxiolytic effect of AA was evaluated using rota-rod and a set of behavioral tests in male Swiss albino mice at the doses of 10, 25, and 50 mg/kg. Flumazenil was used to evaluate the possible involvement of GABAergic system in the mechanism of action of AA. The effect of AA on oxidative stress in mice was evaluated by determining the concentration of malondialdehyde (MDA), reduced glutathione, and catalase (CAT) activity. The detection of DNA damage of the treated animals was performed using alkaline comet test in the hippocampus and frontal cortex of the animals. The results demonstrated that AA did not produce myorelaxant and sedative effects, nor did it cause a decrease in locomotor activity. The anxiolytic effect of AA was well-evident in all tests, especially at higher dose levels (25 and 50 mg/mg). Flumazenil reversed the anxiolytic effect of AA at all doses. In addition, AA reduced oxidative stress by decreasing the concentration of MDA and increasing the levels of reduced glutathione (GSH) and CAT activity. Statistical analysis by Pearson's correlation indicated a positive correlation between anxiolytic effect of AA to its antioxidant and lipid peroxidation inhibitory activity. Furthermore, increased CAT activity and GSH concentrations in the hippocampus and frontal cortex of mice was also complementary to the reduced genotoxic damage observed in the study. In comet assay, AA did not increase in DNA damage. In conclusion, the results supported that AA possesses GABAA receptor mediated anxiolytic activity with the lack of myorelaxation and genotoxicity. © 2018 IUBMB Life, 70(5):420-431, 2018.
Asunto(s)
Ácidos Anacárdicos/farmacología , Anacardium/química , Ansiolíticos/farmacología , Antioxidantes/farmacología , Ansiedad/tratamiento farmacológico , Ácidos Anacárdicos/química , Ácidos Anacárdicos/aislamiento & purificación , Animales , Ansiolíticos/química , Ansiolíticos/aislamiento & purificación , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Ansiedad/metabolismo , Ansiedad/fisiopatología , Catalasa/metabolismo , Diazepam/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Masculino , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos ICR , Nueces/química , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Garcinielliptone FC (GFC) is a polyisoprenylated benzophenone isolated from Platonia insignis Mart (Clusiaceae) with promising anticonvulsant properties. However, its safe use and other effects on the central nervous system require assessment. This study assessed the toxicological effects of GFC using the comet assay and the micronucleus test in mice treated for 28 days. A behavioural model was employed to detect possible injuries on the central nervous system. Mice treated with GFC (2, 10 and 20 mg/kg; i.p.) daily for 28 days were submitted to rotarod test, open-field test and tail suspension test (TST). After the behaviour tasks, biological samples were assessed to evaluate genotoxic and mutagenic effects using the comet assay and the micronucleus test. Garcinielliptone FC did not impair the performance of the animals in the rotarod and open-field tests, with no antidepressant-like effect in TST. No genotoxic effects in blood and cerebral cortex were observable in the comet assay; however, there was a significant increase in index and frequency of damage in liver after treatment with GFC 20 mg/kg. Garcinielliptone FC did not increase micronucleus frequency in bone marrow. At the tested doses, GFC was not toxic to the CNS and did not induce genotoxic damage to blood or bone narrow cells. DNA damage to liver tissue was caused only by the highest dose, although no mutagenic potential was observed.
Asunto(s)
Anticonvulsivantes/toxicidad , Conducta Animal/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Triterpenos/toxicidad , Animales , Anticonvulsivantes/aislamiento & purificación , Clusiaceae/química , Ensayo Cometa , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inyecciones Intraperitoneales , Hígado/efectos de los fármacos , Masculino , Ratones , Pruebas de Micronúcleos , Modelos Animales , Prueba de Desempeño de Rotación con Aceleración Constante , Pruebas de Toxicidad Subaguda , Resultado del Tratamiento , Triterpenos/aislamiento & purificaciónRESUMEN
Anacardic acids (AAs) are alkyl phenols mainly presenting in cashew nuts. The antioxidant effects of these compounds have been an area of interest in recent research, with findings suggesting potential therapeutic use for certain diseases. Nevertheless, none of these studies were performed in order to test the hypothesis of whether anacardic acids are capable of preventing behavioral changes and oxidative stress induced by the pesticide rotenone in experimental model of Parkinson's disease. In our research, adult male rats were treated orally with AAs (1, 3, 10, 25, 50, or 100 mg/kg/day) 1 h before rotenone (3 mg/kg; s.c.) for five consecutive days. The behavioral testing strategies, including tests for general locomotor activity (open field), motor coordination (rotarod), and spatial memory performance (elevated T-maze), were carried out. Lipoperoxidation levels and total superoxide dismutase (t-SOD) activity, as well as cytoplasmic and mitochondrial SOD gene expression, were assessed in the substantia nigra (SN), striatum, and cerebral cortex. The results showed that AAs dose-dependently prevented the rotenone-induced learning and motor impairment from 10 mg/kg/day. AAs also precluded rotenone-induced lipoperoxidation in all doses, acting directly on the mitochondria, and improved the t-SOD activity in the doses 25-100 mg/kg/day. AAs per se (100 mg/kg/day) increased SOD gene expression and t-SOD activity. Our findings indicate that the oral administration of AAs prevents rotenone-induced behavioral changes and oxidative stress, in part due to a modulatory action on the mitochondria and SOD gene expression. These data suggest that AAs have promising neuroprotective action against degenerative changes in Parkinson's disease.