RESUMEN
BACKGROUND: Augmented reality (AR) technology has been shown to be effective in displaying information and presenting three-dimensional objects. Although AR applications are commonly used by learners via mobile devices, plastic models or two-dimensional images are still commonly used in tooth carving practice. Learners practicing tooth carving face a challenge due to the three-dimensional features of teeth as there is a lack of tools available that provide sequential guidance. In this study, we developed an AR-based tooth carving practice tool (AR-TCPT) and compared it to a plastic model to evaluate its potential as a practice tool as well as its user experience. METHODS: To model tooth carving, we created a three-dimensional object from sequential steps that included the maxillary canines and maxillary first premolars (16 steps), mandibular first premolars (13 steps), and mandibular first molars (14 steps). Image markers, created using Photoshop software, were assigned to each tooth. An AR-based mobile application was developed using the Unity engine. For tooth carving, 52 participants were randomly assigned to a control group (n = 26; using a plastic tooth model) or an experimental group (n = 26; using the AR-TCPT). User experience was evaluated using a 22-item questionnaire. Data were comparatively analyzed using the nonparametric Mann-Whitney U test via the SPSS program. RESULTS: The AR-TCPT detects image markers with the mobile device camera and displays three-dimensional objects for tooth fragmentation. Users can manipulate the device to view each step or examine the shape of a tooth. The results of the user experience survey revealed that the AR-TCPT experimental group scored significantly higher in tooth carving experience compared with the control group that used the plastic model. CONCLUSION: Compared with the conventional plastic model, the AR-TCPT provided a better user experience for tooth carving. The tool is highly accessible as it is designed to be used on mobile devices by users. Further studies are required to determine the educational impact of the AR-TCTP on quantitative scoring of carved teeth as well as individual user's carving abilities.
Asunto(s)
Realidad Aumentada , Educación en Odontología , Aplicaciones Móviles , Diente , Computadoras de Mano , Estudios Prospectivos , Diente/anatomía & histología , Modelos Anatómicos , Educación en Odontología/métodos , Estudiantes de Odontología , HumanosRESUMEN
The treatment of neuropathic pain is one of the urgent unmet medical needs and T-type calcium channels are promising therapeutic targets for neuropathic pain. Several potent T-type channel inhibitors showed promising in vivo efficacy in neuropathic pain animal models and are being investigated in clinical trials. Herein we report development of novel pyrrolidine-based T-type calcium channel inhibitors by pharmacophore mapping and structural hybridisation followed by evaluation of their Cav3.1 and Cav3.2 channel inhibitory activities. Among potent inhibitors against both Cav3.1 and Cav3.2 channels, a promising compound 20n based on in vitro ADME properties displayed satisfactory plasma and brain exposure in rats according to in vivo pharmacokinetic studies. We further demonstrated that 20n effectively improved the symptoms of neuropathic pain in both SNL and STZ neuropathic pain animal models, suggesting modulation of T-type calcium channels can be a promising therapeutic strategy for the treatment of neuropathic pain.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Neuralgia/tratamiento farmacológico , Pirrolidinas/farmacología , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Modelos Animales de Enfermedad , Células HEK293 , Humanos , Ligadura , Masculino , Ratones , Ratones Noqueados , Estructura Molecular , Neuralgia/inducido químicamente , Neuralgia/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Ratas Sprague-Dawley , Nervios Espinales/cirugía , EstreptozocinaRESUMEN
This study aimed to examine the anti-diabetic effect of germinated waxy black rice (GWBR) using streptozotocin (STZ)-induced diabetic rats. In the diabetic rats, GWBR supplementation for 8 weeks reduced plasma blood glucose concentrations, improved glucose clearance and prevented diabetes-induced weight loss. Rats with STZ-induced diabetes who received GWBR supplementation exhibited decreased expression of sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter (GLUT) 2 genes and proteins in the small intestine via decreases in hepatocyte nuclear factor (HNF)-1α, HNF-1ß, and HNF-4α, transcriptional factors that are involved in the regulation of SGLT1 and GLUT2, compared with the rats with STZ-induced diabetes that did not receive GWBR supplements. GWBR supplementation also enhanced the expression of GLUT4 and the genes and proteins involved in GLUT4 translocation, such as insulin receptor (IR) and insulin receptor substrate 1 (IRS1), and increased the phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB, Akt) proteins in skeletal muscle. GWBR further increased glycogen synthase (GS) 1 by decreasing glycogen synthase kinase (GSK)-3ß in skeletal muscle. Interestingly, GWBR recovered STZ-impaired pancreatic ß-cells, resulting in increased insulin synthesis and secretion. In addition, GWBR reduced serum triglyceride, total cholesterol, low-density lipoprotein cholesterol, aspartate transferase and alanine transferase concentrations and increased high-density lipoprotein cholesterol concentrations. Taken together, these findings suggest that GWBR could be a candidate for improving the diabetic condition by regulating glucose uptake in the intestine and muscle and regulating the secretion of insulin from the pancreas.
Asunto(s)
Diabetes Mellitus Experimental/dietoterapia , Dislipidemias/dietoterapia , Glucosa/metabolismo , Hiperglucemia/dietoterapia , Insulina/metabolismo , Oryza/química , Animales , Glucemia , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Dislipidemias/sangre , Germinación , Transportador de Glucosa de Tipo 4/metabolismo , Factores Nucleares del Hepatocito/metabolismo , Humanos , Hiperglucemia/sangre , Proteínas Sustrato del Receptor de Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/enzimología , Células Secretoras de Insulina/metabolismo , Intestino Delgado/enzimología , Intestino Delgado/metabolismo , Lípidos/sangre , Masculino , Músculo Esquelético/enzimología , Músculo Esquelético/metabolismo , Oryza/crecimiento & desarrollo , Ratas , Ratas Sprague-Dawley , Receptor de Insulina/metabolismo , Transportador 1 de Sodio-Glucosa/metabolismo , Estreptozocina/toxicidadRESUMEN
Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold. Among these compounds, compound 9b and 10b showed excellent antagonistic activity in vitro and demonstrated pain-suppressing activity in animal models of pain. Both compounds were orally active, and compound 9b exhibited a favorable pharmacokinetic profile in rats. We believe that these compounds can provide a promising lead compound that is suitable for the potential treatment of neuropathic pain.
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Analgésicos/química , Analgésicos/farmacología , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Neuralgia/tratamiento farmacológico , Nitrilos/química , Nitrilos/farmacología , Piridinas/química , Piridinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Analgésicos/administración & dosificación , Analgésicos/farmacocinética , Animales , Células Cultivadas , Células HEK293 , Humanos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Nitrilos/administración & dosificación , Nitrilos/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
There has been much attention to discover mGluR1 antagonists for treating various central nervous system diseases such as seizures and neuropathic pain. Thienopyrimidinone derivatives were designed, synthesized, and biologically evaluated against mGluR1. Among the synthesized compounds, 3-(4-methoxyphenyl)-7-(o-tolyl)thienopyrimidin-4-one 30 exhibited the most potent inhibitory activity with an IC50 value of 45 nM and good selectivity over mGluR5. Also, the selective mGluR1 antagonist 30 showed marginal hERG channel activity (IC50 = 9.87 µM), good profiles to CYP isozymes, and a good pharmacokinetic profile. Overall, the compound 30 was identified as a selective mGluR1 antagonist with a good pharmacokinetic profile, which is probably devoid of cardiac side effect and drug-drug interactions. Therefore, the compound 30 can be expected to be broadly used as mGluR1 antagonistic chemical probe in in vitro and in vivo study for investigating CNS diseases.
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Diseño de Fármacos , Pirimidinonas/química , Pirimidinonas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Concentración 50 InhibidoraRESUMEN
A series of 2-amino and 2-methoxy quinoline-6-carboxamide derivatives have been synthesized and their metabotropic glutamate receptor type 1 (mGluR1) antagonistic activities were evaluated in a functional cell-based assay. The compound 13c showed the highest potency with IC50 value of 2.16 µM against mGluR1. Finally, in vivo evaluation of 13c in the rat spinal nerve ligation (SNL) model exhibited weak analgesic effects with regard to both mechanical allodynia and cold allodynia.
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Neuralgia/tratamiento farmacológico , Piperidinas/farmacología , Quinolinas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Frío , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Hiperalgesia/tratamiento farmacológico , Ratones , Estructura Molecular , Dimensión del Dolor/efectos de los fármacos , Piperidinas/síntesis química , Piperidinas/química , Quinolinas/síntesis química , Quinolinas/química , Ratas , Relación Estructura-ActividadRESUMEN
New tetrahydropyridinyl and piperidinyl ethylamine derivatives were designed with hypothetical mapping on pharmacophore model generated from ligand-based virtual screening. The designed compounds were synthesized, and their inhibitory activities on T-type calcium channel were assayed using FDSS and patch-clamp assay. Among them, compounds 7b and 10b showed potent T-type calcium current blocking activity against Ca(v)3.1 (α(1G)) and Ca(v)3.2 (α(1H)) channel simultaneously. With hERG and pharmacokinetics studies, compounds 7b and 10b were evaluated for the antinociceptive effect on rat model of neuropathic pain. They were significantly effective in decreasing the pain responses to mechanical and cold allodynia induced by spinal nerve ligation. These results suggest that modulation of α(1G) and α(1H) subtype T-type calcium channels may provide a promising approach for the treatment of neuropathic pain.
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Analgésicos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Neuralgia/tratamiento farmacológico , Piperidinas/síntesis química , Piridinas/síntesis química , Analgésicos/uso terapéutico , Animales , Bloqueadores de los Canales de Calcio/uso terapéutico , Evaluación Preclínica de Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , RatasRESUMEN
A novel series of 3-arylsulfonylamino-5,6-dihydro-6-substituted-1H-pyrazolo[3,4-c]pyridine-7-ones was designed and synthesized as 5-HT6 ligands. Among the derivatives synthesized, the lead compound, 12b, having piperidine functionality at the 6-position and (1-naphthyl)sulfonamino at the 3-position of the core structure showed the most potent 5-HT6 inhibitory activity in vitro, good stability without CYP liability, and good neuropathic pain alleviation activity in a rat animal model.
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Piridonas/síntesis química , Piridonas/farmacología , Receptores de Serotonina/metabolismo , Animales , Modelos Animales de Enfermedad , Estabilidad de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Estructura Molecular , Neuralgia/tratamiento farmacológico , Unión Proteica/efectos de los fármacos , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacología , Piridonas/química , RatasRESUMEN
In Parkinson's disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson's disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson's disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure-activity relationship study revealed that the piperidino group was the best choice for the R(1) amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives.
Asunto(s)
Inhibidores de la Monoaminooxidasa/uso terapéutico , Monoaminooxidasa/química , Oxazoles/química , Enfermedad de Parkinson/tratamiento farmacológico , Piridinas/química , Tiazoles/química , Sitios de Unión , Dominio Catalítico , Dopamina/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Monoaminooxidasa/genética , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/patología , Piridinas/síntesis química , Piridinas/uso terapéutico , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-ActividadRESUMEN
We described here the synthesis and biological evaluation of mGluR5 antagonists containing a quinoline ring structure. Using intracellular calcium mobilization assay (FDSS assay), we identified compound 5n, showing high inhibitory activity against mGluR5. In addition, it was found that compound 5n has excellent stability profile. Finally, this compound exhibited favorable analgesic effects in spinal nerve ligation model of neuropathic pain, which is comparable to gabapentin.
Asunto(s)
Acetileno/análogos & derivados , Neuralgia/tratamiento farmacológico , Quinolinas/síntesis química , Quinolinas/farmacología , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Acetileno/química , Acetileno/farmacología , Células HEK293 , Humanos , Quinolinas/químicaRESUMEN
Impairment in spinal inhibition caused by quantitative alteration of GABAergic elements following peripheral nerve injury has been postulated to mediate neuropathic pain. In the present study, we tested whether neuropathic pain could be induced or reversed by pharmacologically modulating spinal GABAergic activity, and whether quantitative alteration of spinal GABAergic elements after peripheral nerve injury was related to the impairment of GABAergic inhibition or neuropathic pain. To these aims, we first analyzed the pain behaviors following the spinal administration of GABA antagonists (1 microg bicuculline/rat and 5 microg phaclofen/rat), agonists (1 microg muscimol/rat and 0.5 microg baclofen/rat) or GABA transporter (GAT) inhibitors (20 microg NNC-711/rat and 1 microg SNAP-5114/rat) into naïve or neuropathic animals. Then, using Western blotting, PCR or immunohistochemistry, we compared the quantities of spinal GABA, its synthesizing enzymes (GAD65, 67) and its receptors (GABA(A) and GABA(B)) and transporters (GAT-1, and -3) between two groups of rats with different severity of neuropathic pain following partial injury of tail-innervating nerves; the allodynic and non-allodynic groups. Intrathecal administration of GABA antagonists markedly lowered tail-withdrawal threshold in naïve animals, and GABA agonists or GAT inhibitors significantly attenuated neuropathic pain in nerve-injured animals. However, any quantitative changes in spinal GABAergic elements were not observed in both the allodynic and non-allodynic groups. These results suggest that although the impairment in spinal GABAergic inhibition may play a role in mediation of neuropathic pain, it is not accomplished by the quantitative change in spinal elements for GABAergic inhibition and therefore these elements are not related to the generation of neuropathic pain following peripheral nerve injury.
RESUMEN
BACKGROUND: Although numerous animal models for low back pain associated with intervertebral disk (IVD) degeneration have been proposed, insufficient data have been provided to make any conclusions regarding pain. Our aim in this study was to determine the reliability of complete Freund's adjuvant (CFA) injection into the rat spine as an animal model representing human discogenic pain. METHODS: We studied IVD degenerative changes with pain development after a 10-microL CFA injection into the L5-6 IVD of adult rats using behavioral, histologic, and biochemical studies. Serial histologic changes were analyzed to detect degenerative changes. Expression of calcitonin gene-related peptide (CGRP), prostaglandin E (PGE), and inducible nitric oxide synthase (iNOS) were determined using immunohistochemistry or real-time polymerase chain reaction as support data for pain development. In addition, CGRP immunoreactivity (ir) at the IVD was considered indirect evidence of neural ingrowth into the IVD. RESULTS: There was a significant increase of the hindpaw withdrawal response in the CFA group until 7 wk postoperatively (P < 0.05). Histologic analyses revealed progressive degenerative changes of the disks without any damage in adjacent structures, including nerve roots. In the CGRP-ir staining study, the bilateral dorsal horns and IVD had positive ir after intradiscal CFA injection. CGRP mRNA expression was increased in the dorsal root ganglion (DRG) at 2 and 4 wk, whereas PGE and iNOS mRNAs were markedly increased at 2 wk. The increment of CGRP expression was higher in allodynic rats compared with nonallodynic rats. CONCLUSION: Intradiscal CFA injection led to chronic disk degeneration with allodynia, which was suggested by pain behavior and expression of pain-related mediators. The increment of CGRP, PGE, and iNOS also suggest pain-related signal processing between the IVD and the neural pathway in this animal model. This animal model may be useful for future research related to the pathophysiology and development of novel treatment for spine-related pain.
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Discitis/complicaciones , Hiperalgesia/etiología , Disco Intervertebral , Dolor de la Región Lumbar/etiología , Vértebras Lumbares , Animales , Conducta Animal , Péptido Relacionado con Gen de Calcitonina/genética , Péptido Relacionado con Gen de Calcitonina/metabolismo , Discitis/inducido químicamente , Discitis/metabolismo , Discitis/patología , Discitis/fisiopatología , Modelos Animales de Enfermedad , Adyuvante de Freund/administración & dosificación , Hiperalgesia/metabolismo , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Inmunohistoquímica , Inyecciones Espinales , Disco Intervertebral/metabolismo , Disco Intervertebral/patología , Disco Intervertebral/fisiopatología , Dolor de la Región Lumbar/metabolismo , Dolor de la Región Lumbar/patología , Dolor de la Región Lumbar/fisiopatología , Vértebras Lumbares/metabolismo , Vértebras Lumbares/patología , Vértebras Lumbares/fisiopatología , Masculino , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Dimensión del Dolor , Umbral del Dolor , Reacción en Cadena de la Polimerasa , Prostaglandinas E/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Transducción de Señal , Factores de Tiempo , Soporte de PesoRESUMEN
The early postnatal period has been suggested to be the vulnerable time for structural and functional reorganization of sensory systems, and painful stimuli at this time may alter neuronal circuits, thereby leading to changes in an individual's response to pain later in life. In the present study, we examined whether inflammatory experience in the early life can affect pain responses to subsequent noxious insults later in life. The two groups of neonatal rats, treated with an inflammatory irritant and untreated, were subjected to inflammation and peripheral nerve injury in adulthood. Neonatal inflammation was induced by injection of complete Freund's adjuvant (CFA, 25 microl) into the hindpaw or tail of newborn rat pups. Adult rats which had suffered from neonatal paw inflammation at P0 were subjected to re-injection of CFA into the paw neonatally exposed to CFA or L5 spinal nerve ligation. Paw thickness and histology of inflamed paw were examined to assess the neonatal inflammation. Adult animals whose tail had been subjected to CFA injection on P3 received tail-innervating nerve injury. The results showed that the neonatal CFA-treated rats suffered from chronic inflammation, confirmed by persistent increase of paw thickness and histological result of inflamed paw. These animals showed enhanced pain responses to re-inflammatory challenge by injection of CFA (200 microl) into the neonatally inflamed paw 8 weeks after birth compared with the neonatally untreated animals. However, neuropathic pain on the hindpaw and the tail which had been induced by peripheral nerve injury in the neonatal CFA-treated group were not different from those of the untreated group. The present data suggest that early neonatal long-lasting inflammation differentially affects pain responses later in life, depending on the types of subsequent noxious insults.
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Animales Recién Nacidos , Inflamación/fisiopatología , Dolor/fisiopatología , Traumatismos de los Nervios Periféricos , Animales , Conducta Animal/fisiología , Femenino , Adyuvante de Freund/efectos adversos , Masculino , Nervios Periféricos/fisiología , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Thimet oligopeptidase (EC 3.4.24.15) and neurolysin (EC 3.4.24.16) are closely related zinc-dependent metallopeptidases that metabolize small bioactive peptides. They cleave many substrates at the same sites, but they recognize different positions on others, including neurotensin, a 13-residue peptide involved in modulation of dopaminergic circuits, pain perception, and thermoregulation. On the basis of crystal structures and previous mapping studies, four sites (Glu-469/Arg-470, Met-490/Arg-491, His-495/Asn-496, and Arg-498/Thr-499; thimet oligopeptidase residues listed first) in their substrate-binding channels appear positioned to account for differences in specificity. Thimet oligopeptidase mutated so that neurolysin residues are at all four positions cleaves neurotensin at the neurolysin site, and the reverse mutations in neurolysin switch hydrolysis to the thimet oligopeptidase site. Using a series of constructs mutated at just three of the sites, it was determined that mutations at only two (Glu-469/Arg-470 and Arg-498/Thr-499) are required to swap specificity, a result that was confirmed by testing the two-mutant constructs. If only either one of the two sites is mutated in thimet oligopeptidase, then the enzyme cleaves almost equally at the two hydrolysis positions. Crystal structures of both two-mutant constructs show that the mutations do not perturb local structure, but side chain conformations at the Arg-498/Thr-499 position differ from those of the mimicked enzyme. A model for differential recognition of neurotensin based on differences in surface charge distribution in the substrate binding sites is proposed. The model is supported by the finding that reducing the positive charge on the peptide results in cleavage at both hydrolysis sites.