Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system(CNS)injury.The glial scar has been proposed as a major contributor to this failure in the ...Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system(CNS)injury.The glial scar has been proposed as a major contributor to this failure in the regenerative process.However,its underlying molecular and cellular mechanisms remain unclear.Here,we report that monoamine oxidase B(MAOB)-dependent excessiveγ-aminobutyric acid(GABA)release from reactive astrocytes suppresses the CNS repair system by reducing brain‒derived neurotrophic factor(BDNF)and tropomyosin receptor kinase B(TrkB)expression in severe spinal cord injury(SCI)animal models.Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery.Notably,the selective MAOB inhibitor,KDS2010,facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model.Its dose-dependent effects were further validated in a monkey SCI model.Moreover,KDS2010 demonstrated a tolerable safety profile and doseproportional pharmacokinetics in healthy humans during a phase 1 clinical trial.This pathway therefore represents a pivotal target for overcoming the intrinsic barriers to CNS repair after injury.Our findings identify the astrocytic MAOB‒GABA axis as a crucial molecular and cellular brake on the CNS repair system following SCI and highlight the translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.展开更多
Post-traumatic stress disorder(PTSD)remains a debilitating psychiatric condition with limited pharmacological treatment options.Identifying novel therapeutic targets is critical for addressing its unmet clinical needs...Post-traumatic stress disorder(PTSD)remains a debilitating psychiatric condition with limited pharmacological treatment options.Identifying novel therapeutic targets is critical for addressing its unmet clinical needs.Through our comprehensive human clinical research,including both cross-sectional and longitudinal studies,we revealed a compelling link between dysregulated prefrontal gamma-aminobutyric acid(GABA)levels and PTSD symptoms.Notably,elevated prefrontal GABA levels in PTSD patients are associated with impaired cerebral blood flow(CBF)and symptom severity,normalizing with recovery,highlighting GABA dysregulation as a key mechanism in the disorder.Postmortem and PTSD-like mouse models implicated monoamine oxidase B(MAOB)-dependent astrocytic GABA as a primary driver of this imbalance,exacerbating deficit in fear extinction retrieval.展开更多
Hemoglobin(Hb)is well known for transporting oxygen in the blood,but its role in the brain remains poorly understood.Here,we identified Hb in the cytosol,mitochondria,and nuclei of hippocampal and substantia nigra ast...Hemoglobin(Hb)is well known for transporting oxygen in the blood,but its role in the brain remains poorly understood.Here,we identified Hb in the cytosol,mitochondria,and nuclei of hippocampal and substantia nigra astrocytes and dopaminergic neurons.As a pseudoperoxidase,Hb decomposes hydrogen peroxide(H_(2)O_(2))and mitigates H_(2)O_(2)-induced oxidative damage.However,in Alzheimer’s disease,Parkinson’s disease,and aging,excessive H_(2)O_(2) diminishes astrocytic Hb,perpetuating a vicious cycle of oxidative stress and neurodegeneration.To counter the harmful effects of aberrant H_(2)O_(2) production in diseases,we developed KDS12025,a BBB-permeable small molecule that enhances Hb pseudoperoxidase activity 100-fold,even at a low level of Hb.KDS12025 and its analogs achieve this enhancement through its electron-donating amine group,possibly stabilizing the complex between Hb,H_(2)O_(2),and KDS12025.KDS12025 reduces astrocytic H_(2)O_(2),alleviates astrogliosis,normalizes Hb,and reverts to a virtuous cycle of redox balance,preventing neurodegeneration without altering the oxygen-transport function of Hb.Gene silencing of Hb abrogates the impact of KDS12025 in both culture and animal models,confirming the necessity of Hb for the effects of KDS12025.KDS12025 extends survival and improves motor function even in severe amyotrophic lateral sclerosis and aging.Furthermore,the enrichment of astrocytic Hb in the nucleolus highlights a novel antioxidative mechanism potentially protecting against nuclear oxidative damage.Our findings suggest that Hb is a new therapeutic target for neurodegenerative diseases,with KDS12025 emerging as a first-in-class approach that enhances Hb pseudoperoxidase activity to reduce H_(2)O_(2).Increasing Hb pseudoperoxidase activity with KDS12025 mitigates oxidative stress and alleviates neurodegeneration in AD,PD,and ALS patients and increases the degree of aging,with broad applicability for numerous oxidative-stress-driven diseases.展开更多
基金supported by a faculty research grant from Yonsei University College of Medicine(6-2018-0161)the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(RS-2024-00341308)+1 种基金the Center for Cognition and Sociality from Institute for Basic Science(IBS)(IBS-R001-D2)and NeuroBiogen Co.,LTD.
文摘Neuroregeneration and remyelination rarely occur in the adult mammalian brain and spinal cord following central nervous system(CNS)injury.The glial scar has been proposed as a major contributor to this failure in the regenerative process.However,its underlying molecular and cellular mechanisms remain unclear.Here,we report that monoamine oxidase B(MAOB)-dependent excessiveγ-aminobutyric acid(GABA)release from reactive astrocytes suppresses the CNS repair system by reducing brain‒derived neurotrophic factor(BDNF)and tropomyosin receptor kinase B(TrkB)expression in severe spinal cord injury(SCI)animal models.Genetic deletion of MAOB in a mouse SCI model promotes both functional and tissue recovery.Notably,the selective MAOB inhibitor,KDS2010,facilitates recovery and regeneration by disinhibiting the BDNF-TrkB axis in a rat SCI model.Its dose-dependent effects were further validated in a monkey SCI model.Moreover,KDS2010 demonstrated a tolerable safety profile and doseproportional pharmacokinetics in healthy humans during a phase 1 clinical trial.This pathway therefore represents a pivotal target for overcoming the intrinsic barriers to CNS repair after injury.Our findings identify the astrocytic MAOB‒GABA axis as a crucial molecular and cellular brake on the CNS repair system following SCI and highlight the translational potential of KDS2010 as a promising therapeutic candidate for SCI treatment.
基金supported by National Research Foundation of Korea grants funded by the Ministry of Science and ICT(RS-2024-00457381 to I.K.L.2020M3E5D9079742 to H.R.)+2 种基金by the Ministry of Education(2020R1A6A1A03043528 to I.K.L.)This work was also in part supported by the Institute for Basic Science(IBS),Center for Cognition and Sociality(IBS-R001-D2 to C.J.L)This project applied tools developed under NIH grants R01 EB016089,R01 EB023963 and P41 EB031771.
文摘Post-traumatic stress disorder(PTSD)remains a debilitating psychiatric condition with limited pharmacological treatment options.Identifying novel therapeutic targets is critical for addressing its unmet clinical needs.Through our comprehensive human clinical research,including both cross-sectional and longitudinal studies,we revealed a compelling link between dysregulated prefrontal gamma-aminobutyric acid(GABA)levels and PTSD symptoms.Notably,elevated prefrontal GABA levels in PTSD patients are associated with impaired cerebral blood flow(CBF)and symptom severity,normalizing with recovery,highlighting GABA dysregulation as a key mechanism in the disorder.Postmortem and PTSD-like mouse models implicated monoamine oxidase B(MAOB)-dependent astrocytic GABA as a primary driver of this imbalance,exacerbating deficit in fear extinction retrieval.
基金Institute for Basic Science(IBS),Center for Cognition and Sociality(IBS-R001-D2 to C.J.L.)Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI)and Korea Dementia Research Center(KDRC),funded by the Ministry of Health&Welfare and Ministry of Science and ICT,Republic of Korea(HU23C0018 to K.D.P.+3 种基金RS-2023-KH137130 to H.R.)Korea Institute of Science and Technology(KIST)Institutional Program(2E32851 to K.D.P.)National Research Foundation(NRF)grant funded by the Korea government(MSIT)(RS-2023-00261784 to A.N.P.,2022R1A2C3013138 to H.R.)Supercomputing resources were provided by the Korea Institute of Science and Technology Information(KISTI-HPC)(KSC-2023-CRE-0420 to A.N.P.).
文摘Hemoglobin(Hb)is well known for transporting oxygen in the blood,but its role in the brain remains poorly understood.Here,we identified Hb in the cytosol,mitochondria,and nuclei of hippocampal and substantia nigra astrocytes and dopaminergic neurons.As a pseudoperoxidase,Hb decomposes hydrogen peroxide(H_(2)O_(2))and mitigates H_(2)O_(2)-induced oxidative damage.However,in Alzheimer’s disease,Parkinson’s disease,and aging,excessive H_(2)O_(2) diminishes astrocytic Hb,perpetuating a vicious cycle of oxidative stress and neurodegeneration.To counter the harmful effects of aberrant H_(2)O_(2) production in diseases,we developed KDS12025,a BBB-permeable small molecule that enhances Hb pseudoperoxidase activity 100-fold,even at a low level of Hb.KDS12025 and its analogs achieve this enhancement through its electron-donating amine group,possibly stabilizing the complex between Hb,H_(2)O_(2),and KDS12025.KDS12025 reduces astrocytic H_(2)O_(2),alleviates astrogliosis,normalizes Hb,and reverts to a virtuous cycle of redox balance,preventing neurodegeneration without altering the oxygen-transport function of Hb.Gene silencing of Hb abrogates the impact of KDS12025 in both culture and animal models,confirming the necessity of Hb for the effects of KDS12025.KDS12025 extends survival and improves motor function even in severe amyotrophic lateral sclerosis and aging.Furthermore,the enrichment of astrocytic Hb in the nucleolus highlights a novel antioxidative mechanism potentially protecting against nuclear oxidative damage.Our findings suggest that Hb is a new therapeutic target for neurodegenerative diseases,with KDS12025 emerging as a first-in-class approach that enhances Hb pseudoperoxidase activity to reduce H_(2)O_(2).Increasing Hb pseudoperoxidase activity with KDS12025 mitigates oxidative stress and alleviates neurodegeneration in AD,PD,and ALS patients and increases the degree of aging,with broad applicability for numerous oxidative-stress-driven diseases.
