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
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.
