RESUMEN
Cordycepin, an adenosine analog, has been reported to improve cognitive function, but which seems to be inconsistent with the reports showing that cordycepin inhibited long-term potentiation (LTP). Behavioral-LTP is usually used to study long-term synaptic plasticity induced by learning tasks in freely moving animals. In order to investigate simultaneously the effects of cordycepin on LTP and behavior in rats, we applied the model of behavioral-LTP induced by Y-maze learning task through recording population spikes in hippocampal CA1 region. Golgi staining and Sholl analysis were employed to assess the morphological structure of dendrites in pyramidal cells of hippocampal CA1 area, and western blotting was used to examine the level of adenosine A1 receptors and A2A receptors (A2AR). We found that cordycepin significantly improved behavioral-LTP magnitude, accompanied by increases in the total length of dendrites, the number of intersections and spine density but did not affect Y-maze learning task. Furthermore, cordycepin obviously reduced A2AR level without altering adenosine A1 receptors level; and the agonist of A2AR (CGS 21680) rather than antagonist (SCH 58261) could reverse the potentiation of behavioral-LTP induced by cordycepin. These results suggested that cordycepin improved behavioral-LTP and morphological structure of dendrite in hippocampal CA1 but did not contribute to the improvement of learning and memory. And cordycepin improved behavioral-LTP may be through reducing the level of A2AR in hippocampus. Collectively, the effects of cordycepin on cognitive function and LTP were complex and involved multiple mechanisms.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Dendritas/efectos de los fármacos , Desoxiadenosinas/farmacología , Potenciación a Largo Plazo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Animales , Masculino , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Although nanoparticles carriers for oral delivery of insulin have been researched for many years, this method still fails to solve issues with toxicity, biocompatibility, and degradability in the organism. We therefore developed an innovative conjugation system to solve this problem. Nano hydroxyapatite (HAP) particles were used as the core, then polyethylene glycol (PEG) was wrapped onto the surface of hydroxyapatite, and, finally, insulin (INS) and gallic acid (GA) were conjugated with PEG. PEG functionalized HAP was increased the hydrophilicity of the nanoparticles, also protected them from degradation in the gastrointestinal (GI) tract. Most importantly, the in vivo absorption of nanoparticles in rat small intestines revealed that HAP-PEG-GA-INS was absorbed by the small intestine epithelium. The blood glucose of the type 1 diabetes (T1D) rats that were given intragastrically HAP-PEG-GA-INS showed an obvious downward trend. Overall, we synthesized a safe, non-toxic, and effective oral insulin delivery system.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Durapatita/química , Ácido Gálico/química , Insulina/administración & dosificación , Nanopartículas/administración & dosificación , Administración Oral , Animales , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/metabolismo , Células Hep G2 , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/química , Insulina/química , Nanopartículas/química , Polietilenglicoles/química , RatasRESUMEN
Parkinson's disease (PD) is second most common neurodegenerative disorder worldwide. Although drugs and surgery can relieve the symptoms of PD, these therapies are incapable of fundamentally treating the disease. For PD patients, over-expression of α-synuclein (SNCA) leads to the death of dopaminergic neurons. This process can be prevented by suppressing SNCA over-expression through RNA interference. Here, we successfully synthesized gold nanoparticles (GNP) composites (CTS@GNP-pDNA-NGF) via the combination of electrostatic adsorption and photochemical immobilization, which could load plasmid DNA (pDNA) and target specific cell types. GNP was transfected into cells via endocytosis to inhibiting the apoptosis of PC12 cells and dopaminergic neurons. Simultaneously, GNP composites are also used in PD models in vivo, and it can successfully cross the blood-brain barrier by contents of GNP in the mice brain. In general, all the works demonstrated that GNP composites have good therapeutic effects for PD models in vitro and in vivo.
Asunto(s)
Oro/química , Nanopartículas del Metal/química , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Humanos , Ratones , Factor de Crecimiento Nervioso/química , Enfermedad de Parkinson/metabolismo , Plásmidos/genéticaRESUMEN
Although L-type voltage-dependent calcium channels (VDCCs) have been reported to display different even contrary actions on cognitive functions and long-term potentiation (LTP) formation, there is little information regarding the role of L-type VDCCs in behavioral LTP, a learning-induced LTP model, in the intact brain of freely behaving animals. Here we investigated the effects of verapamil, a non-selective blocker of L-type VDCCs, on behavioral LTP and cognitive functions. Population spikes (PS) were recorded by using electrophysiological methods to examine the role of verapamil in behavioral LTP in the hippocampal dentate gyrus (DG) region. Y-maze assay was used to evaluate the effects of verapamil on learning and memory. Electron microscope was used to observe the changes on synaptic ultrastructural morphology in hippocampal DG area. We found that intrahippocampal verapamil treatments had no significant changes on the PS amplitude during a 90min recordings period. However, intrahippocampal applications of verapamil, including pre- or post-training, reduced behavioral LTP magnitude and memory retention but did not prevent the induction of behavioral LTP and the acquisition of learning. The saline group with behaving trainings showed obvious increases in the number of smile synapses, the length of active zones and the thickness of postsynaptic density as compared to the baseline group, but verapamil with pre-training treatment almost returned these changes to the baseline levels except for the synaptic interface curvature. In conclusion, our results suggest that L-type VDCCs may only contribute to the magnitude of behavioral LTP and the memory maintenance with an activity-independent relationship. L-type VDCCs may be critical to new information long-term storage rather than acquisition in hippocampus.
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Canales de Calcio Tipo L/fisiología , Giro Dentado/fisiología , Potenciación a Largo Plazo , Retención en Psicología/fisiología , Animales , Bloqueadores de los Canales de Calcio/administración & dosificación , Giro Dentado/efectos de los fármacos , Giro Dentado/ultraestructura , Masculino , Ratas Sprague-Dawley , Sinapsis/ultraestructura , Verapamilo/administración & dosificaciónRESUMEN
Obtusifolin, an anthraquinone from Cassia obtusifolia seeds, has been reported to reduce blood lipid levels in diabetic rats induced by streptozocin. However, it remains unclear whether obtusifolin possesses a lipid-lowering effect on hyperlipidemia caused by a high-fat diet. Moreover, hyperlipidemia is known to impair the endothelial function by causing oxidative stress. Therefore, in the present study, we investigated the antidyslipidemic and antioxidant effects of obtusifolin in hyperlipidemic rats induced by a high-fat diet. Rats with oral fat emulsion were used as our hyperlipidemic model. We measured the body weight of the rats, serum total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, as well as nitric oxide, malondialdehyde, and superoxide dismutase. Our results showed that oral obtusifolin application significantly reversed the changes induced by hyperlipidemia in body weight, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Furthermore, obtusifolin treatment increased serum superoxide dismutase and nitric oxide, but reduced malondialdehyde. Collectively, our findings suggest that obtusifolin may improve hyperlipidemia by enhancing antioxidant activity. This study indicates a potential therapeutic importance of obtusifolin for ameliorating lipid dysfunction induced by a high-fat diet.
Asunto(s)
Antraquinonas/farmacología , Antioxidantes/farmacología , Hiperlipidemias/dietoterapia , Lípidos/sangre , Administración Oral , Animales , Antraquinonas/administración & dosificación , Peso Corporal/efectos de los fármacos , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Dieta Alta en Grasa/efectos adversos , Suplementos Dietéticos , Hiperlipidemias/sangre , Hiperlipidemias/etiología , Masculino , Malondialdehído/sangre , Óxido Nítrico/sangre , Ratas Sprague-Dawley , Superóxido Dismutasa/sangre , Triglicéridos/sangreRESUMEN
GABAB receptor is present at pre- and post-synaptic sites and participates in many brain functions including cognition, reward and anxiety. Although a lot of research has shown that activation or blockade of GABAB receptor may produce different even opposing effects on long-term potentiation (LTP) and cognitive function, there is little information available concerning the effect of GABAB receptor on behavioral LTP, a learning-induced LTP model. Herein, we firstly examined the effects of 2-OH saclofen, a GABAB receptor antagonist, on the induction of behavioral LTP and Y-maze learning performance. In addition, GABAB receptor has been reported to be present on cholinergic terminals and to regulate the ACh release. Therefore, we also investigated the effect of 2-OH saclofen on the impairments in behavioral LTP and cognitive function induced by scopolamine, an acetylcholine receptor antagonist. We found that intrahippocampal application of 2-OH saclofen could significantly enhance the population spike (PS) amplitude with a dose-response relationship, and 20 µM 2-OH saclofen evidently facilitated the formation of behavioral LTP in the perforant pathway to the dentate gyrus (PP-DG) and led to an obvious improvement in maze learning performance. Furthermore, intrahippocampal 20 µM 2-OH saclofen administration could markedly reverse the scopolamine-induced impairments in behavioral LTP and maze performance. Our data demonstrate that blockade of GABAB receptor displays a facilitatory role in the induction of behavioral LTP and maze learning task, and the antagonist of GABAB receptor seems to exert the potentially therapeutic value in the cognitive defect induced by cholinergic dysfunction.
Asunto(s)
Baclofeno/análogos & derivados , Antagonistas de Receptores de GABA-B/farmacología , Hipocampo/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Animales , Baclofeno/farmacología , Cognición/efectos de los fármacos , Masculino , Ratas Sprague-DawleyRESUMEN
Polygala tenuifolia Wild is an ancient traditional Chinese medicine. Its main component, tenuifolin (TEN), has been proven to improve cognitive impairment caused by neurodegenerative diseases and ovariectomy. However, there was hardly any pharmacological research about TEN and its potential gender differences. Considering the reduction of TEN on learning and memory dysfunction in ovariectomized animals, therefore, we focused on the impact of TEN in different mice genders in the current study. Spontaneous alternation behavior (SAB), light-dark discrimination, and Morris water maze (MWM) tests were used to evaluate the mice's learning and memory abilities. The field excitatory postsynaptic potential (fEPSP) of the hippocampal CA1 region was recorded using an electrophysiological method, and the morphology of the dendritic structure was examined using Golgi staining. In the behavioral experiments, TEN improved the correct rate in female mice in the SAB test, the correct rate in the light-dark discrimination test, and the number of crossing platforms in the MWM test. Additionally, TEN reduced the latency of female mice rather than male mice in light-dark discrimination and MWM tests. Moreover, TEN could significantly increase the slope of fEPSP in hippocampal Schaffer-CA1 and enhance the total length and the number of intersections of dendrites in the hippocampal CA1 area in female mice but not in male mice. Collectively, the results of the current study showed that TEN improved learning and memory by regulating long-term potentiation (LTP) and dendritic structure of hippocampal CA1 area in female mice but not in males. These findings would help to explore the improvement mechanism of TEN on cognition and expand the knowledge of the potential therapeutic value of TEN in the treatment of cognitive impairment.
Asunto(s)
Región CA1 Hipocampal , Dendritas , Diterpenos de Tipo Kaurano , Potenciación a Largo Plazo , Animales , Femenino , Masculino , Región CA1 Hipocampal/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Ratones , Dendritas/efectos de los fármacos , Memoria/efectos de los fármacos , Factores Sexuales , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiologíaRESUMEN
Ischemic stroke is a neurological disease that leads to brain damage and severe cognitive impairment. In this study, extracellular vesicles(Ev) derived from mouse hippocampal cells (HT22) were used as carriers, and adenosine (Ad) was encapsulated to construct Ev-Ad to target the damaged hippocampus. The results showed that, Ev-Ad had significant antioxidant effect and inhibited apoptosis. In vivo, Ev-Ad reduced cell death and reversed inflammation in hippocampus of ischemic mice, and improved long-term memory and learning impairment by regulating the expression of the A1 receptor and the A2A receptor in the CA1 region. Thus, the developmental approach based on natural carriers that encapsulating Ad not only successfully restored nerves after ischemic stroke, but also improved cognitive impairment in the later stage of ischemic stroke convalescence. The development and design of therapeutic drugs provides a new concept and method for the treatment of cognitive impairment in the convalescent phase after ischemic stroke.
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Vesículas Extracelulares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Animales , Ratones , Adenosina/farmacología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Hipocampo , Vesículas Extracelulares/metabolismo , Cognición , Accidente Cerebrovascular Isquémico/metabolismoRESUMEN
BACKGROUND: Parkinson's disease (PD), the most common neurodegenerative disorder, primarily affects dopaminergic neurons in the substantia nigra (SN). In addition to severe motor dysfunction, PD patients appear apparent cognitive impairments in the late stage. Cognitive dysfunction is accompanied by synaptic transmission damage in the hippocampus. Cordycepin has been reported to alleviate cognitive impairments in neurodegenerative diseases. PURPOSE: The study aimed to estimate the protection roles of cordycepin on cognitive dysfunction in PD model and explore the potential mechanisms. METHODS: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to establish the PD model in vivo and in vitro experiments. In the in vivo experiments, the C57BL / 6 mice were intraperitoneally injected with MPTP and intragastric administration with cordycepin. Open field test (OFT) was used to estimate the exercise ability. Spontaneous alternation behavioral (SAB) and morris water maze (MWM) tests were used to evaluate the learning and memory abilities. The hippocampal slices from C57BL / 6 and Kunming mice in the in vitro experiments were used to record field excitatory postsynaptic potential (fEPSP) by electrophysiological methods. Western blotting was used to examine the level of tyrosine hydroxylase (TH) in the in vivo experiments and the levels of adenosine A1 and A2A receptors (A1R and A2AR) in the in vitro experiments, respectively. The drugs of MPTP, cordycepin, DPCPX and SCH58261 were perfused through dissolving in artificial cerebrospinal fluid. RESULTS: Cordycepin could significantly reduce the impairments on motor, exploration, spatial learning and memory induce by MPTP. MPTP reduced the amplitude of LTP in hippocampal CA1 area but cordycepin could improve LTP amplitudes. Cordycepin at dosage of 20 mg/kg also increased the TH level in SN. In the in vitro experiments, MPTP inhibited synaptic transmission in hippocampal Schaffer-CA1 pathway with a dose-dependent relationship, while cordycepin could reverse the inhibition of synaptic transmission. Furthermore, the roles of cordycepin on synaptic transmission could been attenuated in the presence of the antagonists of A1R and A2AR, DPCPX and SCH58261, respectively. Interestingly, the level of A2AR rather than A1R in hippocampus was significantly decreased in the cordycepin group as compared to the control. CONCLUSION: The present study has showed that cordycepin could improve cognitive function in the PD model induced by MPTP through regulating the adenosine A2A receptors. These findings were helpful to provide a new strategy for the dementia caused by Parkinson's disease.
Asunto(s)
Enfermedad de Parkinson , Animales , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Adenosina , Cognición , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
Parkinson's disease (PD) always causes dyskinesia and cognitive impairments. The alpha-synuclein (α-syn) accumulation, one of the main pathological characteristics of PD, may impair synaptic structural and synaptic functions. Nano-MgO composites has been reported to interfere α-syn expression. The present study is aim to investigate the roles of nano-MgO composites on cognitive impairments in PD rats. PD rats were formed by 6-hydroxydopamine (6-OH DA) and α-syn expression were evaluated by Western blot. Hippocampal dendritic morphology was examined by Golgi staining. Morris water maze (MWM) test was applied to evaluate learning and memory abilities and population spike was recorded by electrophysiological records in vivo. The results showed that: 6-OH DA-treated up-regulated α-syn levels in striatum and hippocampus and increased the rotational times by APO, but nano-MgO composites could down-regulated α-syn levels. The overall length of dendritic and the total number of intersections were reduced by 6-OH DA, accompanied by the decrease of the dendritic spine density in hippocampal CA1, CA3 and DG regions. Interestingly, nano-MgO composites could alleviate the morphological damages of dendrites. In the MWM test, the escape latencies and the swimming distances in PD rats were increased as compared to the sham group, and nano-MgO composites could reduce the escapes latencies and the swimming distances. Furthermore, 6-OH DA reduced the amplitudes of long-term potentiation (LTP) in hippocampal CA1 region, and 6 mg/kg nano-MgO composites could improve LTP amplitudes. In conclusion, the current findings would be helpful to explore the roles of nano-MgO composites on neuroprotection in PD.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , ADN , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Oxidopamina , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Plásmidos , Ratas , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Cordycepin exerted significant neuroprotective effects and protected against cerebral ischemic damage. Learning and memory impairments after cerebral ischemia are common. Cordycepin has been proved to improve memory impairments induced by cerebral ischemia, but its underlying mechanism has not been revealed yet. The plasticity of synaptic structure and function is considered to be one of the neural mechanisms of learning and memory. Therefore, we investigated how cordycepin benefits dendritic morphology and synaptic transmission after cerebral ischemia and traced the related molecular mechanisms. The effects of cordycepin on the protection against ischemia were studied by using global cerebral ischemia (GCI) and oxygen-glucose deprivation (OGD) models. Behavioral long-term potentiation (LTP) and synaptic transmission were observed with electrophysiological recordings. The dendritic morphology and histological assessment were assessed by Golgi staining and hematoxylin-eosin (HE) staining, respectively. Adenosine A1 receptors (A1R) and adenosine A2A receptors (A2AR) were evaluated with western blotting. The results showed that cordycepin reduced the GCI-induced dendritic morphology scathing and behavioral LTP impairment in the hippocampal CA1 area, improved the learning and memory abilities, and up-regulated the level of A1R but not A2AR. In the in vitro experiments, cordycepin pre-perfusion could alleviate the hippocampal slices injury and synaptic transmission cripple induced by OGD, accompanied by increased adenosine content. In addition, the protective effect of cordycepin on OGD-induced synaptic transmission damage was eliminated by using an A1R antagonist instead of A2AR. These findings revealed that cordycepin alleviated synaptic dysfunction and dendritic injury in ischemic models by modulating A1R, which provides new insights into the pharmacological mechanisms of cordycepin for ameliorating cognitive impairment induced by cerebral ischemia.
RESUMEN
Metaplasticity is referred to adjustment in the requirements for induction of synaptic plasticity based on the prior history of activity. Synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), has been considered to be the neural processes underlying learning and memory. Previous observations that cordycepin (an adenosine derivative) improved learning and memory seemed to be contradictory to the findings that cordycepin inhibited LTP. Therefore, we speculated that the conflicting reports of cordycepin might be related to metaplasticity. In the current study, population spike (PS) in hippocampal CA1 area of rats was recorded by using electrophysiological method in vivo. The results showed that cordycepin reduced PS amplitude in hippocampal CA1 with a concentration-dependent relationship, and high frequency stimulation (HFS) failed to induce LTP when cordycepin was intrahippocampally administrated but improved LTP magnitude when cordycepin was pre-treated. Cordycepin increased LTD induced by activating N-Methyl-D-aspartate (NMDA) receptors and subsequently facilitated LTP induced by HFS. Furthermore, we found that 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an adenosine A1 receptors antagonist, could block the roles of cordycepin on LTD and LTP. Collectively, cordycepin was able to modulate metaplasticity in hippocampal CA1 area of rats through adenosine A1 receptors. These findings would be helpful to reconcile the conflicting reports in the literatures and provided new insights into the mechanisms underlying cognitive function promotions with cordycepin treatment.
Asunto(s)
Agonistas del Receptor de Adenosina A1/farmacología , Región CA1 Hipocampal/efectos de los fármacos , Desoxiadenosinas/farmacología , Plasticidad Neuronal/efectos de los fármacos , Receptor de Adenosina A1/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Región CA1 Hipocampal/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Receptor de Adenosina A1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de TiempoRESUMEN
Although gene therapy targeting the α-synuclein gene (SNCA) has achieved outstanding results in the treatment of Parkinson's disease (PD), the lack of a suitable gene delivery system and inadequate therapeutic effects remains a tremendous obstacle for RNAi therapy. Here, a degradable nano-MgO micelle composite (MgO(pDNA)-INS-Plu-mRNA-NGF) with double interference (mediated by RNAi and α-synuclein (α-syn)-targeted mRNA) was constructed. Binding mRNA treatment significantly increased the inhibitory effect compared to the reduction of α-syn expression by RNAi alone. Moreover, the cell experiments demonstrated that the viability of the PD cell model can be significantly improved by nano-MgO micelle composite treatment. More importantly, the composite has the ability to penetrate the blood brain barrier and deliver genes and mRNA to neurons through endocytosis mediated by the nerve growth factor and its receptors, thus significantly downregulating the expression of α-syn in the PD mice model without causing damage to other major organs. Overall, this work provides a novel insight into the design of biomaterials for gene therapy for PD.
Asunto(s)
Enfermedad de Parkinson , Animales , Ratones , Micelas , Neuronas/metabolismo , Enfermedad de Parkinson/terapia , Interferencia de ARN , alfa-Sinucleína/genéticaRESUMEN
Parkinson's disease (PD) is characterized by motor and non-motor symptoms, primarily affecting dopaminergic neurons (DAergic neurons) in substantia nigra (SN). However, it is still very challenging to identify new drugs that not only inhibit motor dysfunction but also improve non-motor dysfunction. It has been identified as a potential PD treatment that the inhibition of α-syn aggregation could decrease the death of DAergic neurons in SN. In this study, we synthesized gold nanoparticle composites (NPs) that were loaded with plasmid DNA (pDNA) to inhibit α-syn expression. In vivo, our results showed that NPs improved tyrosine hydroxylase (TH) levels and decreased aggregation of α-syn in the SN. Additionally, NPs attenuated motor dysfunction and exploration ability declined. Moreover, NPs reversed the inhibition of long-term potentiation (LTP) and improved non-motor dysfunction in PD mice. These results indicated that NPs had significantly neuroprotective effects not only in motor, but also in non-motor dysfunction to PD mice, providing a new strategy for gene therapy in PD.
Asunto(s)
Disfunción Cognitiva , Nanopartículas del Metal , Enfermedad de Parkinson , Animales , Modelos Animales de Enfermedad , Oro , Ratones , Ratones Endogámicos C57BL , Enfermedad de Parkinson/tratamiento farmacológico , Sustancia NegraRESUMEN
Cerebral ischemia impairs physiological form of synaptic plasticity such as long-term potentiation (LTP). Clinical symptoms of cognitive dysfunction resulting from cerebral ischemia are associated with neuron loss and synaptic function impairment in hippocampus. It has been widely reported that cordycepin displays neuroprotective effect on ameliorating cognitive dysfunction induced by cerebral ischemia. Therefore, it is necessary to study whether cordycepin recovers cognitive function after brain ischemia through improving LTP induction. However, there has been very little discussion about the effects of cordycepin on LTP of cerebral ischemia so far. In the present study, we investigated the effects of cordycepin on LTP impairment and neuron loss induced by cerebral ischemia and excitotoxicity, using electrophysiological recording and Nissl staining techniques. The models were obtained by bilateral common carotid artery occlusion (BCCAO) and intrahippocampal NMDA microinjection. We also explored whether adenosine A1 receptors involve in the neuroprotection of cordycepin by using western blot. We found that cordycepin remarkably alleviated LTP impairment and protected pyramidal cell of hippocampal CA1 region against cerebral ischemia and excitotoxicity. Meanwhile, cordycepin prevented the reduction on adenosine A1 receptor level caused by ischemia but did not alter the adenosine A2A receptor level in hippocampal CA1 area. The improvement of LTP in the excitotoxic rats after cordycepin treatment could be blocked by DPCPX, a selective antagonist of adenosine A1 receptor. In summary, our findings provided new insights into the mechanisms of cordycepin neuroprotection in excitotoxic diseases, which is through regulating adenosine A1 receptor to improve LTP formation and neuronal survival.
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Desoxiadenosinas/farmacología , N-Metilaspartato/toxicidad , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Receptor de Adenosina A1/metabolismo , Animales , Recuento de Células , Regulación de la Expresión Génica/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Neuronas/citología , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos , Sinapsis/fisiologíaRESUMEN
Cordycepin, an adenosine analogue, has been reported to improve cognitive function. Important roles on learning and memory of adenosine and its receptors, such as adenosine A1 and A2A receptors (A1R and A2AR), also have been shown. Therefore, we assume that the improvement of learning and memory induced by cordycepin is likely related to hippocampal adenosine content and adenosine receptor density. Here we investigated the effects of cordycepin on the short-term spatial memory by using a spontaneous alternation behavior (SAB) test in Y-maze, and then examined hippocampal adenosine content and A1R and A2AR densities. We found that orally administrated cordycepin (at dosages of 5 and 10mg/kg twice daily for three weeks) significantly increased the percent of relative alternation of mice in SAB but not altered body weight, hippocampus weight and hippocampal adenosine content. Furthermore, cordycepin decreased A2AR density in hippocampal subareas; however, cordycepin only reduced the A1R density in DG but not CA1 or CA3 region. Our results suggest that cordycepin exerts a nootropic role possibly through modulating A2AR density of hippocampus, which further support the concept that it is mostly A2AR rather than A1R to control the adaptive processes of memory performance. These findings would be helpful to provide a new window into the pharmacological properties of cordycepin for cognitive promotion.
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Desoxiadenosinas/farmacología , Hipocampo/efectos de los fármacos , Nootrópicos/farmacología , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Memoria Espacial/efectos de los fármacos , Adenosina/farmacología , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/anatomía & histología , Hipocampo/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Estadísticas no Paramétricas , Factores de TiempoRESUMEN
Oral drug delivery has attracted substantial attention due to its advantages over other administration routes. Bacillus spores, as oral probiotic agents, are applied widely. In this paper, a novel Bacillus spore-based oral colon targeted carrier loading curcumin was developed for colon cancer treatment. Curcumin was linked covalently with the outer coat of Bacillus spore and folate, respectively (SPORE-CUR-FA). Bacillus spores are capable of delivering drugs to the colon area through gastric barrier, taking the advantage of its tolerance to the harsh conditions and disintegration of the outer coat of spores after germination in the colon. The drug release in vitro and in vivo of SPORE-CUR-FA was investigated. Results showed that SPORE-CUR-FA had the characteristics of colon-targeted drug release. Pharmacokinetic studies confirmed that Bacillus spore-based carriers could efficiently improve the oral bioavailability of curcumin. In vitro and in vivo anti-tumor studies showed that SPORE-CUR-FA had substantial ability for inhibiting colon cancer cells. These findings suggest that this Bacillus spore-based oral drug delivery system has a great potential for the treatment of colon cancer.
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Antineoplásicos/administración & dosificación , Bacillus coagulans , Neoplasias del Colon/tratamiento farmacológico , Curcumina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Ácido Fólico/administración & dosificación , Esporas Bacterianas , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Curcumina/química , Curcumina/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Ácido Fólico/química , Ácido Fólico/farmacocinética , Células HT29 , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To study the protective effects of tenuigenin (TEN) on the PC12 cells injury induced by H2O2. METHODS: Oxidative damage PC12 cells model was induced by H2O2. The survival rate of the cells was determined by MTT method. The content of LDH was determined by ultraviolet spectrophometry and the content of MDA and SOD activity was measured respectively by thiobarbituric acid and xanthine oxidese method. RESULTS: tenuigenin could reduce obviously cells injury induced by H2O2. 10 mg L(-1) tenuigenin could improve the cells survival rate, reduce LDH releasing and MDA content, increase SOD activity. CONCLUSION: tenuigenin have significantly potective effect on the PC12 cells injury induced by H2O2.
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Medicamentos Herbarios Chinos/farmacología , Peróxido de Hidrógeno/toxicidad , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Recuento de Células , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , L-Lactato Deshidrogenasa/metabolismo , Malondialdehído/metabolismo , Células PC12 , Polygalaceae/química , Ratas , Superóxido Dismutasa/metabolismoRESUMEN
Lewy bodies are considered as the main pathological characteristics of Parkinson's disease (PD). The major component of Lewy bodies is α-synuclein (α-syn). The use of gene therapy that targeting and effectively interfere with the expression of α-syn in neurons has received tremendous attention. In this study, we used magnetic Fe3O4 nanoparticles coated with oleic acid molecules as a nano-carrier. N-isopropylacrylamide derivative (NIPAm-AA) was photo-immobilized onto the oleic acid molecules, and shRNA (short hairpin RNA) was absorbed. The same method was used to absorb nerve growth factor (NGF) to NIPAm-AA to specifically promote neuronal uptake via NGF receptor-mediated endocytosis. Additionally, shRNA plasmid could be released into neurons because of the temperature and pH sensitivity of NIPAm-AA interference with α-syn synthesis. We investigated apoptosis in neurons with abrogated α-syn expression in vitro and in vivo. The results demonstrated that multifunctional superparamagnetic nanoparticles carrying shRNA for α-syn could provide effective repair in a PD model.
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Productos Biológicos/administración & dosificación , Terapia Genética/métodos , Nanopartículas de Magnetita/administración & dosificación , Enfermedad de Parkinson/terapia , Plásmidos/administración & dosificación , ARN Interferente Pequeño/administración & dosificación , alfa-Sinucleína/antagonistas & inhibidores , Acrilamidas/administración & dosificación , Animales , Modelos Animales de Enfermedad , Portadores de Fármacos/administración & dosificación , Endocitosis , Masculino , Ratones Endogámicos C57BL , Factor de Crecimiento Nervioso/administración & dosificación , Neuronas/fisiología , ARN Interferente Pequeño/genética , alfa-Sinucleína/genéticaRESUMEN
Synthesis of artificial and functional structures for bone tissue engineering has been well recognized but the associated cell senescence issue remains much less concerned so far. In this work, surface-modified polycaprolactone-polylactic acid scaffolds using self-assembled heterojunction carbon nanotubes (sh-CNTs) combined with insulin-like growth factor-1 are synthesized and a series of structural and biological characterizations are carried out, with particular attention to cell senescence mechanism. It is revealed that the modified scaffolds can up-regulate the expressions of alkaline phosphates and bone morphogenetic proteins while down-regulate the expressions of senescence-related proteins in mesenchymal stem cells, demonstrating the highly preferred anti-senescence functionality of the sh-CNTs modified scaffolds in bone tissue engineering. Furthermore, it is also found that with sh-CNTs, scaffolds can accelerate bone healing with extremely low toxicity in vivo.