Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain. Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular...Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain. Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular space but these still remain unknown. Herein,effects of the inhalational isoflurane, intravenous sedative dexmedetomidine and pentobarbital sodium on deep brain matters’ interstitial fluid drainage and extracellular space and underlying mechanisms were investigated. When compared to intravenous anesthetic dexmedetomidine or pentobarbital sodium, inhalational isoflurane induced a restricted diffusion of extracellular space, a decreased extracellular space volume fraction, and an increased norepinephrine level in the caudate nucleus or thalamus with the slowdown of brain interstitial fluid drainage. A local administration of norepinephrine receptor antagonists, propranolol,atipamezole and prazosin into extracellular space increased diffusion of extracellular space and interstitial fluid drainage whilst norepinephrine decreased diffusion of extracellular space and interstitial fluid drainage. These findings suggested that restricted diffusion in brain extracellular space can cause slowdown of interstitial fluid drainage, which may contribute to the neurotoxicity following the waste accumulation in extracellular space under inhaled anesthesia per se.展开更多
Ischemic stroke is a leading cause of death and disability worldwide.Inflammatory response after stroke determines the outcome of ischemic injury.A recent study has reported an efficient method,epidural arterial impla...Ischemic stroke is a leading cause of death and disability worldwide.Inflammatory response after stroke determines the outcome of ischemic injury.A recent study has reported an efficient method,epidural arterial implantation(EAI),for accelerating interstitial fluid(ISF)drainage,which provides a promising strategy to clear pro-inflammatory cytokines in the brain extracellular space(ECS).In this study,the method of EAI was modified(m-EAI)to control its function of accelerating the ISF drainage at different time points following ischemic attack.The neuroprotective effect of m-EAI on ischemic stroke was evaluated with the transient middle cerebral artery occlusion(tMCAO)rat model.The results demonstrated the accumulation of IL-1β,IL-6,and TNF-αwas significantly decreased by activating m-EAI at 7 d before and immediately after ischemic attack in tMCAO rats,accompanied with decreased infarct volume and improved neurological function.This study consolidates the hypothesis of exacerbated ischemic damage by inflammatory response and provides a new perspective to treat encephalopathy via brain ECS.Further research is essential to investigate whether m-EAI combined with neuroprotective drugs could enhance the therapeutic effect on ischemic stroke.展开更多
The extracellular space(ECS) of brain is defined as an irregular channel which is located in the interstitial tissue outside the plasma membranes of neurons,and occupied by interstititial fluid(ISF).Diffusion in ECS i...The extracellular space(ECS) of brain is defined as an irregular channel which is located in the interstitial tissue outside the plasma membranes of neurons,and occupied by interstititial fluid(ISF).Diffusion in ECS is described by a modified diffusion equation from which several parameters can be calculated,such as the diffusion coefficient(D),the tortuosity(λ),the volume fraction(α) and the clearance of molecules.Radiolabeled tracers were used for early diffusion measurements.Presently,the real-time iontophoresis(RTI) method is employed for small ions,whereas the integrative optical imaging(IOI) and the magnetic resonance diffusion weighted imaging(DWI) are developed for macromolecules tracers.Extensive experimental studies with such methods show that in normal brain tissue,the volume fraction of ECS typically is about 20% and the tortuosity is 1.6,although there are regional variations.These parameters change with the brain development and in various pathophysiological states.Knowledge of ECS diffusion properties help us to understand extrasynaptic volume transmission to the development of paradigms for drug delivery in brain.展开更多
The smooth transportation of substances through the brain extracellular space(ECS)is crucial to maintaining brain function;however,the way this occurs under simulated microgravity remains unclear.In this study,tracer-...The smooth transportation of substances through the brain extracellular space(ECS)is crucial to maintaining brain function;however,the way this occurs under simulated microgravity remains unclear.In this study,tracer-based magnetic resonance imaging(MRI)and DECS-mapping techniques were used to image the drainage of brain interstitial fluid(ISF)from the ECS of the hippocampus in a tail-suspended hindlimb-unloading rat model at day 3(HU-3)and 7(HU-7).The results indicated that drainage of the ISF was accelerated in the HU-3 group but slowed markedly in the HU-7 group.The tortuosity of the ECS decreased in the HU-3 group but increased in the HU-7 group,while the volume fraction of the ECS increased in both groups.The diffusion rate within the ECS increased in the HU-3 group and decreased in the HU-7 group.The alterations to ISF drainage and diffusion in the ECS were recoverable in the HU-3 group,but neither parameter was restored in the HU-7 group.Our findings suggest that early changes to the hippocampal ECS and ISF drainage under simulated microgravity can be detected by tracer-based MRI,providing a new perspective for studying microgravity-induced nano-scale structure abnormities and developing neuroprotective approaches involving the brain ECS.展开更多
基金supported by the National Major Scientific Research Instrument Development Project(61827808)the National Key Basic Research Program(973 Program,2015CB856402)+2 种基金Beijing Brain Initiative of Beijing Municipal Science&Technology Commission(Z181100001518004)National Natural Science Foundation of China(81872051)Peking University Clinical Scientist Program(BMU2019LCKXJ007)。
文摘Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain. Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular space but these still remain unknown. Herein,effects of the inhalational isoflurane, intravenous sedative dexmedetomidine and pentobarbital sodium on deep brain matters’ interstitial fluid drainage and extracellular space and underlying mechanisms were investigated. When compared to intravenous anesthetic dexmedetomidine or pentobarbital sodium, inhalational isoflurane induced a restricted diffusion of extracellular space, a decreased extracellular space volume fraction, and an increased norepinephrine level in the caudate nucleus or thalamus with the slowdown of brain interstitial fluid drainage. A local administration of norepinephrine receptor antagonists, propranolol,atipamezole and prazosin into extracellular space increased diffusion of extracellular space and interstitial fluid drainage whilst norepinephrine decreased diffusion of extracellular space and interstitial fluid drainage. These findings suggested that restricted diffusion in brain extracellular space can cause slowdown of interstitial fluid drainage, which may contribute to the neurotoxicity following the waste accumulation in extracellular space under inhaled anesthesia per se.
基金supported by the Major Program of the National Natural Science Foundation of China(62394310,62394313,62394314)the National Natural Science Foundation of China(12126601)+5 种基金the R&D project of Pazhou Lab(Huangpu)(2023K0608)the China Postdoctoral Science Foundation(2022M720294)Intelligent Basic Theory Innovation Research fund(201CXCY-A01-08-00-29)GuangDong Basic and Applied Basic Research Foundation(2022A1515110674)Medical Scientific Research Foundation of Guangdong Province of China(B2022067)Science Foundation of AMHT(2021YK11)。
文摘Ischemic stroke is a leading cause of death and disability worldwide.Inflammatory response after stroke determines the outcome of ischemic injury.A recent study has reported an efficient method,epidural arterial implantation(EAI),for accelerating interstitial fluid(ISF)drainage,which provides a promising strategy to clear pro-inflammatory cytokines in the brain extracellular space(ECS).In this study,the method of EAI was modified(m-EAI)to control its function of accelerating the ISF drainage at different time points following ischemic attack.The neuroprotective effect of m-EAI on ischemic stroke was evaluated with the transient middle cerebral artery occlusion(tMCAO)rat model.The results demonstrated the accumulation of IL-1β,IL-6,and TNF-αwas significantly decreased by activating m-EAI at 7 d before and immediately after ischemic attack in tMCAO rats,accompanied with decreased infarct volume and improved neurological function.This study consolidates the hypothesis of exacerbated ischemic damage by inflammatory response and provides a new perspective to treat encephalopathy via brain ECS.Further research is essential to investigate whether m-EAI combined with neuroprotective drugs could enhance the therapeutic effect on ischemic stroke.
文摘The extracellular space(ECS) of brain is defined as an irregular channel which is located in the interstitial tissue outside the plasma membranes of neurons,and occupied by interstititial fluid(ISF).Diffusion in ECS is described by a modified diffusion equation from which several parameters can be calculated,such as the diffusion coefficient(D),the tortuosity(λ),the volume fraction(α) and the clearance of molecules.Radiolabeled tracers were used for early diffusion measurements.Presently,the real-time iontophoresis(RTI) method is employed for small ions,whereas the integrative optical imaging(IOI) and the magnetic resonance diffusion weighted imaging(DWI) are developed for macromolecules tracers.Extensive experimental studies with such methods show that in normal brain tissue,the volume fraction of ECS typically is about 20% and the tortuosity is 1.6,although there are regional variations.These parameters change with the brain development and in various pathophysiological states.Knowledge of ECS diffusion properties help us to understand extrasynaptic volume transmission to the development of paradigms for drug delivery in brain.
基金supported by the National Science Fund for Distinguished Young Scholars(61625102)the National Natural Science Foundation of China(61971011)。
文摘The smooth transportation of substances through the brain extracellular space(ECS)is crucial to maintaining brain function;however,the way this occurs under simulated microgravity remains unclear.In this study,tracer-based magnetic resonance imaging(MRI)and DECS-mapping techniques were used to image the drainage of brain interstitial fluid(ISF)from the ECS of the hippocampus in a tail-suspended hindlimb-unloading rat model at day 3(HU-3)and 7(HU-7).The results indicated that drainage of the ISF was accelerated in the HU-3 group but slowed markedly in the HU-7 group.The tortuosity of the ECS decreased in the HU-3 group but increased in the HU-7 group,while the volume fraction of the ECS increased in both groups.The diffusion rate within the ECS increased in the HU-3 group and decreased in the HU-7 group.The alterations to ISF drainage and diffusion in the ECS were recoverable in the HU-3 group,but neither parameter was restored in the HU-7 group.Our findings suggest that early changes to the hippocampal ECS and ISF drainage under simulated microgravity can be detected by tracer-based MRI,providing a new perspective for studying microgravity-induced nano-scale structure abnormities and developing neuroprotective approaches involving the brain ECS.
