RESUMEN
Ischemic stroke is one of the leading causes of death and disability worldwide. The severe sequelae caused by ischemic thrombolysis and the narrow time window are now the main clinical challenges. Our previous study has reported 4-Trifluoromethyl-(E)-cinnamoyl]-L-4-F-phenylalanine Acid (AE-18) was a promising candidate for Parkinson's Disease. In this study, the preventive and therapeutic effects of AE-18 on focal cerebral ischemia-reperfusion injury and the mechanisms are explored. In oxygen glucose deprivation/reoxygenation (OGD/R)-induced well-differentiated PC12 cells model, AE-18 (10 or 20 µM) can significantly reduce nerve damage when administered before or after molding. In middle cerebral artery occlusion-reperfusion (MCAO/R) rat model, pre-modelling, or post-modelling administration of AE-18 (5 or 10 mg/kg) was effective in reducing neurological damage, decreasing infarct volume and improving motor disturbances. In addition, AE-18 (5 mg/kg) given by intravenous injection immediately after occlusion significantly reduce the infarct volume caused by reperfusion for different durations, indicating that AE-18 could extend the time window of thrombolytic therapy. Further studies demonstrate that AE-18 exerts the effects in the prevention, treatment, and prolongation of the time window of cerebral ischemic injury mainly through inhibiting excitotoxicity and improving BBB permeability, VEGF and BDNF. These results suggest that AE-18 is a good candidate for the treatment of ischemic stroke.
Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Fenilalanina , Daño por Reperfusión , Animales , Isquemia Encefálica/tratamiento farmacológico , Fibrinolíticos/uso terapéutico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Isquemia/complicaciones , Fármacos Neuroprotectores/uso terapéutico , Fenilalanina/farmacología , Fenilalanina/uso terapéutico , Ratas , Reperfusión/efectos adversos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & controlAsunto(s)
Catecoles/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Tirosina/análogos & derivados , Apoptosis/efectos de los fármacos , Catecoles/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Relación Estructura-Actividad , Tirosina/síntesis química , Tirosina/química , Tirosina/farmacologíaRESUMEN
Vascular dementia (VaD), one of the major consequences after stroke, is the second reason for the cognitive decline in aged people. Chronic cerebral hypoperfusion (CCH) is considered as the main cause for cognitive impairment in VaD patients. In our previous study, a synthetic compound, 4-trifluoromethyl-(E)-cinnamoyl]-L-4-F-phenylalanine acid (AE-18), has been proven to decrease infarct volume and to recover the insufficient blood supply after ischemia-reperfusion in rats, which was reminded that AE-18 may possess the ameliorative effect in CCH. In this study, the bilateral common carotid artery occlusion was performed to establish the CCH model in rats to evaluate the effect and mechanisms of AE-18 in CCH. Results showed that AE-18 (5 and 10 mg/kg, i.g.) could recover the learning and memory and increase the number of neurons in the hippocampus, which may be attributed to its neurogenesis effects and its recovery of cerebral blood flow in CCH rats. In addition, the in vitro studies showed that AE-18 promoted neuronal proliferation, induced differentiation of Neuro-2a cells into a neuron-like morphology, and accelerated the establishment of axon-dendrite polarization of primary hippocampal neurons through upregulating brain-derived neurotrophic factor via the PI3K/Akt/CREB pathway. In conclusion, AE-18 is a promising candidate for the treatment of cognitive decline after CCH injury by restoring blood supply to the brain and promoting neurogenesis in the hippocampus.
Asunto(s)
Isquemia Encefálica , Demencia Vascular , Animales , Ratas , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fenilalanina/metabolismo , Neurogénesis , Isquemia Encefálica/metabolismo , Hipocampo/metabolismo , Aprendizaje por Laberinto , Modelos Animales de EnfermedadRESUMEN
N-Phenylpropenoyl-l-amino acids (NPAs) are inducible nitric oxide synthase (iNOS) inhibitors possessing preventive effects for Parkinson's disease (PD). Here, structural modifications for improving the iNOS inhibitory activity and blood-brain barrier (BBB) permeability of NPAs were conducted, leading to 20 optimized NPA derivatives (1-20). Compound 18, with the most potent activity (IC50 = 74 nM), high BBB permeability (Pe = 19.1 × 10-6 cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that 18 directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of 18 (1 and 2 mg/kg) exerted preventive effects by alleviating the loss of dopaminergic (DAergic) neurons. Notably, in the MPTP-/probenecid-induced chronic PD model, the same dose of 18 also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made 18 a promising candidate for the treatment of PD.
Asunto(s)
Aminoácidos/química , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Propanoles/química , Aminoácidos/metabolismo , Aminoácidos/farmacología , Animales , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Diseño de Fármacos , Semivida , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/patología , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Microglía/citología , Microglía/efectos de los fármacos , Microglía/metabolismo , Simulación del Acoplamiento Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Relación Estructura-ActividadRESUMEN
BACKGROUND: Blue light can directly penetrate the lens and reach the retina to induce retinal damage, causing dry age-related macular degeneration (dAMD). Cynaroside (Cyn), a flavonoid glycoside, was proved to alleviate the oxidative damage of retinal cells in vitro. However, whether or not Cyn also exerts protective effect on blue light-induced retinal degeneration and its mechanisms of action are unclear. PURPOSE: This study aims to evaluate the protective effects of Cyn against blue-light induced retinal degeneration and its underlying mechanisms in vitro and in vivo. STUDY DESIGN/METHODS: Blue light-induced N-retinylidene-N-retinylethanolamine (A2E)-laden adult retinal pigment epithelial-19 (ARPE-19) cell damage and retinal damage in SD rats were respectively used to evaluate the protective effects of Cyn on retinal degeneration in vitro and in vivo. MTT assay and AnnexinV-PI double staining assay were used to evaluate the in vitro efficacy. Histological analysis, TUNEL assay, and fundus imaging were conducted to evaluate the in vivo efficacy. ELISA assay, western blot, and immunostaining were performed to investigate the mechanisms of action of Cyn. RESULTS: Cyn decreased the blue light-induced A2E-laden ARPE-19 cell damage and oxidative stress. Intravitreal injection of Cyn (2, 4 µg/eye) reversed the retinal degeneration induced by blue light in SD rats. Furthermore, Cyn inhibited the nuclear translocation of NF-κB and induced autophagy, which led to the clearance of overactivated pyrin domain containing 3 (NLRP3) inflammasome in vitro and in vivo. CONCLUSION: Cyn protects against blue light-induced retinal degeneration by modulating autophagy and decreasing the NLRP3 inflammasome.
Asunto(s)
Apoptosis/efectos de los fármacos , Glucósidos/farmacología , Luteolina/farmacología , Sustancias Protectoras/farmacología , Degeneración Retiniana/tratamiento farmacológico , Animales , Apoptosis/fisiología , Autofagia/efectos de los fármacos , Línea Celular , Glucósidos/administración & dosificación , Humanos , Inflamasomas/metabolismo , Inyecciones Intravítreas , Luz/efectos adversos , Luteolina/administración & dosificación , Masculino , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/administración & dosificación , Ratas Sprague-Dawley , Degeneración Retiniana/etiología , Degeneración Retiniana/patología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/patologíaRESUMEN
A series of clovamide analogues, namely, 1a-13a and 1b-13b, was synthesized and evaluated for their anti-neuroinflammatory activities using BV-2 microglia cells. Among these compounds, six (1b, 4b-8b) showed NO inhibition with no or weak cytotoxicity (CC50â¯>â¯100⯵M), especially 4b, and showed an IC50 value of 2.67⯵M. Enzyme activity and docking assay revealed that the six compounds, especially 4b, target inducible NO synthase (iNOS) and exhibit potent inhibitory effects on iNOS with IC50 values ranging from 1.01⯵M to 29.23⯵M 4b significantly suppressed the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated cells. Notably, the oral administration of 4b remarkably improved dyskinesia, reduced the expression of glial fibrillary acidic protein (GFAP)-a marker of neuroinflammation, and increased tyrosine hydroxylase-positive cells in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine-induced Parkinson's disease (PD) mouse models. These observations demonstrated that 4b is an effective and promising candidate for PD therapy.