Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar format...Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar formation.Current antiepileptic drugs remain ineffective in targeting these mechanisms due to limited blood-brain barrier(BBB)permeability and poor astrocytic specificity.A transferrin-functionalized biomimetic nanotherapeutic loaded with resveratrol(RN@RTA)was developed to regulate astrocyte-mediated inflammation by activating sirtuin 1(SIRT1)and suppressing the mitogen-activated protein kinase/nuclear factor Kappalight-chain-enhancer of activated B cells(MAPK/NF-κB)axis.Using in vitro BBB models,primary astrocytes,and a pilocarpine-induced chronic epilepsy mouse model,we evaluated the capacity of RN@RTA to cross the BBB,inhibit inflammatory signaling,and reduce seizure activity.Mechanistic assays included immunoprecipitation of NF-κB complexes,cytokine quantification,RNA sequencing,and histopathological assessments of glial and synaptic markers.RN@RTA achieved 82%uptake by hippocampal astrocytes and significantly reduced Il6,Tnf-α,and Nlrp3 expression.SIRT1 activation disrupted the NF-κB p65/p300 complex,leading to transcriptional repression of inflammatory genes and enhancement of autophagy.In vivo,seizure frequency decreased by 67%,synaptic structure was preserved,and astrogliosis was markedly alleviated.The findings demonstrate a dual regulatory mechanism in which RN@RTA suppresses neuroinflammatory signaling and restores neural homeostasis,offering a promising molecularly targeted approach for refractory epilepsy.展开更多
基金supported by the Health Commission of Hubei Province scientific research project(No.WJ2021M143)the Fundamental Research Funds for the Central Universities(No.413000714)+2 种基金the Research Fund of Anhui Institute of translational medicine(No.2023zhyx-C61)the Research Fund Project of Anhui Medical University(No.2022xkj148)Hubei Society of Pathology General Project(No.2025HBAP013).
文摘Epilepsy is a complex neurological disorder aggravated by chronic neuroinflammation largely driven by reactive astrocytes.These cells promote epileptogenesis through persistent cytokine secretion and glial scar formation.Current antiepileptic drugs remain ineffective in targeting these mechanisms due to limited blood-brain barrier(BBB)permeability and poor astrocytic specificity.A transferrin-functionalized biomimetic nanotherapeutic loaded with resveratrol(RN@RTA)was developed to regulate astrocyte-mediated inflammation by activating sirtuin 1(SIRT1)and suppressing the mitogen-activated protein kinase/nuclear factor Kappalight-chain-enhancer of activated B cells(MAPK/NF-κB)axis.Using in vitro BBB models,primary astrocytes,and a pilocarpine-induced chronic epilepsy mouse model,we evaluated the capacity of RN@RTA to cross the BBB,inhibit inflammatory signaling,and reduce seizure activity.Mechanistic assays included immunoprecipitation of NF-κB complexes,cytokine quantification,RNA sequencing,and histopathological assessments of glial and synaptic markers.RN@RTA achieved 82%uptake by hippocampal astrocytes and significantly reduced Il6,Tnf-α,and Nlrp3 expression.SIRT1 activation disrupted the NF-κB p65/p300 complex,leading to transcriptional repression of inflammatory genes and enhancement of autophagy.In vivo,seizure frequency decreased by 67%,synaptic structure was preserved,and astrogliosis was markedly alleviated.The findings demonstrate a dual regulatory mechanism in which RN@RTA suppresses neuroinflammatory signaling and restores neural homeostasis,offering a promising molecularly targeted approach for refractory epilepsy.
