Oral 4-aminopyridine(4-AP)is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral n...Oral 4-aminopyridine(4-AP)is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral nerve injury including the promotion of re-myelination,improvement of nerve conductivity,and acceleration of functional recovery.We hypothesized that,instead of oral or injection administration,transdermal 4-AP(TD-4-AP)could also improve functional recovery after traumatic peripheral nerve injury.Mice with surgical traumatic peripheral nerve injury received TD-4AP or vehicle alone and were examined for skin permeability,pharmacokinetics,functional,electrophysiological,and nerve morphological properties.4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to TD-4-AP dose.While a single dose of TD-4-AP administration demonstrated rapid transient improvement in motor function,chronic TD-4-AP treatment significantly improved motor function and nerve conduction and these effects were associated with fewer degenerating axons and thicker myelin sheaths than those from vehicle controls.These findings provide direct evidence for the potential transdermal applicability of 4-AP and demonstrate that 4-AP delivered through the skin can enhance in-vivo functional recovery and nerve conduction while decreasing axonal degeneration.The animal experiments were approved by the University Committee on Animal Research(UCAR)at the University of Rochester(UCAR-2009-019)on March 31,2017.展开更多
4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated tha...4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP(10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research(UCAR) at the University of Rochester(UCAR-2009-019) on March 31, 2017.展开更多
We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect ...We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.展开更多
The binding interactions between 4-aminopyridine(4-AP) and a series of cucurbit[n]urils(Q[5], Q[6],TMe Q[6], Q[7], Q[8]) have been studied using1H NMR spectroscopy, UV–vis absorption spectroscopy,isothermal titration...The binding interactions between 4-aminopyridine(4-AP) and a series of cucurbit[n]urils(Q[5], Q[6],TMe Q[6], Q[7], Q[8]) have been studied using1H NMR spectroscopy, UV–vis absorption spectroscopy,isothermal titration calorimetry(ITC) and X-ray crystallography. The data indicates that the Q[5]@4-AP complex exhibits exo binding, which is not observed in the other four host-guest complexes. Furthermore,X-ray crystallography clearly reveals how the Q[n]s bind with 4-AP to form complexes, for example Q[5]forms an outer-surface complex, whilst Q[6], TMe Q[6] and Q[7] formed 1:1 host and guest type complexes, and Q[8] formed a stable 1:2 ternary complex due to its large cavity, which can accommodate two 4-AP molecules.展开更多
Objective To research the direct electrophysiological evidence of discomplete spinal cord injury (SCI) and the effect of 4-aminopyridine on it.Methods Motor evoked potentials (MEPs), both spinal cord recorded MEPs (...Objective To research the direct electrophysiological evidence of discomplete spinal cord injury (SCI) and the effect of 4-aminopyridine on it.Methods Motor evoked potentials (MEPs), both spinal cord recorded MEPs (scMEPs) and extracellularly recorded MEPs (exMEPs) were recorded and characterized on a T13 epidural electrode (scMEPs) and an extracellular microelectrode (exMEPs) for 10 normal rats and 40 rats with lesions of various severity (sham, 35?g*cm force (gcf), 70?gcf, 100?gcf impact injury) at the T8-T9 cord using the Allen's drop model. The incline plane and Tarlov techniques were used to assess clinical neurological function. Results MEPs in the normal rats were elicited by applying transcortical suprathreshold stimulation consisting of 3-4 early negative peaks (N1, N2, N3 and N4) followed by several late waves. The N1 and N2 peaks were largest in the anterior and ventrolateral funiculus, respectively, which was indicative of extrapyramidal pathways. The 100?gcf impact injuries and the cord transection abolished the MEP distal to the lesion, whereas the 35?gcf injuries resulted in a latency shift and amplitude decrement of the MEP peaks. Eighteen of the 20 rats with 70?gcf injuries showed clinical paraplegia. Among them, 7 rats had neurophysiological evidence of residual conduction pathways through the lesioned cord segment, such as the presence of N1 and N2 peaks in the scMEPs or exMEPs. After 4-aminopyridine (4-AP) administrations (1?mg/kg), the amplitude of the spared exMEP increased significantly and spread more widely. Conclusions MEPs evoked by transcortical stimulation travel mostly in the extrapyramidal tract. MEP monitoring could provide an excellent method of detecting the functional integrity of the motor tracts after SCI, and could even detect spared motor fibers after discomplete SCI. Furthermore, the use of 4-AP or other K+ channel blocking agents may be a potential treatment for patients with chronic moderate to severe SCI.展开更多
A three-dimensional complex [Cu（3-ampy）（HEO）4]（SO4）·（H2O） （3-ampy = 3-amino- pyridine） has been synthesized. Crystallographic data： C5H16CuN2O9S, Mr = 343.80, triclinic, space group P1, a = 7.675（2）,...A three-dimensional complex [Cu（3-ampy）（HEO）4]（SO4）·（H2O） （3-ampy = 3-amino- pyridine） has been synthesized. Crystallographic data： C5H16CuN2O9S, Mr = 343.80, triclinic, space group P1, a = 7.675（2）, b = 8.225（3）, c = 10.845（3）A, α= 86.996（4）, β = 76.292（4）, γ= 68.890（4）°, V = 620.0（3）A^3, Z = 2, Dc = 1.841 g/cm^3, F（000） = 354 and μ = 1.971 mm^-1. The structure was refined to R = 0.0269 and wR = 0.0659 for 1838 observed reflections （I 〉 2a（/））. The structure consists of [Cu（3-ampy）（H2O）4]^2＋ cations, SO4^2- anions and lattice water molecules. 3-Ampy acting as a bidentate bridging ligand generates a 1D covalent chain. A supramolecular 2D framework is formed through π-π stacking of pyridine rings. The lattice water molecules and SO4^2- anions are located between the adjacent 2D frameworks. The hydrogen bonding interactions from lattice water molecules and SO4^2- anions to coordinate water extend the 2D framework into a 3D network.展开更多
Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidati...Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.展开更多
Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterize...Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterized by the infiltration of auto reactive lymphocytes specific to myelin through the blood-brain barrier,which results in the appearance of inflammatory demyelinating lesions caused by the death of the central nervous system myelinating cells,oligodendrocytes(Oh et al.,2018).There is a prevalence sexual with a ratio of three times more affected women than men.展开更多
Geometry optimization of p-C_(6)H_(4)-connected cyclo[20]carbon(p-C_(6)H_(4)-C_(20))was carried out at M062X/6-311G(d,p)level,three kinds of bond orders(Mayer,Laplacian,and Wiberg),electron-hole distributions,localize...Geometry optimization of p-C_(6)H_(4)-connected cyclo[20]carbon(p-C_(6)H_(4)-C_(20))was carried out at M062X/6-311G(d,p)level,three kinds of bond orders(Mayer,Laplacian,and Wiberg),electron-hole distributions,localized orbital locators(LOL),and infrared(IR)spectrum were also performed at the same level.Based on TD-DFT M062X/6-311G(d,p)method,the first 20 excited states and ultraviolet(UV)spectra of p-C_(6)H_(4)-C_(20) were calculated.Calculation results of π-electron delocalization analyses prove thatπ-electron delocalization of p-C_(6)H_(4)-C_(20) is more likely to occur on shorter C-C bonds rather than longer C-C bonds,and inside/outside of the ring plane rather than above/below the ring plane.Two absorption peaks of p-C_(6)H_(4)-C_(20) locate at about 319 nm and 236 nm,respectively.展开更多
Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism rem...Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.展开更多
基金supported by grants from the National Institutes of Health(K08 AR060164-01A)Department of Defense(W81XWH-16-1-0725)to JCE in addition to institutional support from the University of Rochester and Pennsylvania State University Medical Centers
文摘Oral 4-aminopyridine(4-AP)is clinically used for symptomatic relief in multiple sclerosis and we recently demonstrated that systemic 4-AP had previously unknown clinically-relevant effects after traumatic peripheral nerve injury including the promotion of re-myelination,improvement of nerve conductivity,and acceleration of functional recovery.We hypothesized that,instead of oral or injection administration,transdermal 4-AP(TD-4-AP)could also improve functional recovery after traumatic peripheral nerve injury.Mice with surgical traumatic peripheral nerve injury received TD-4AP or vehicle alone and were examined for skin permeability,pharmacokinetics,functional,electrophysiological,and nerve morphological properties.4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to TD-4-AP dose.While a single dose of TD-4-AP administration demonstrated rapid transient improvement in motor function,chronic TD-4-AP treatment significantly improved motor function and nerve conduction and these effects were associated with fewer degenerating axons and thicker myelin sheaths than those from vehicle controls.These findings provide direct evidence for the potential transdermal applicability of 4-AP and demonstrate that 4-AP delivered through the skin can enhance in-vivo functional recovery and nerve conduction while decreasing axonal degeneration.The animal experiments were approved by the University Committee on Animal Research(UCAR)at the University of Rochester(UCAR-2009-019)on March 31,2017.
基金supported by grants from the National Institutes of Health(NIHK08 AR060164-01A)+2 种基金the Department of Defense(DoDW81XWH-16-1-0725)to JCEinstitutional support from the University of Rochester and Pennsylvania State University Medical Centers。
文摘4-Aminopyridine(4-AP), an FDA-approved drug for the symptomatic treatment of multiple sclerosis, is used to improve neuromuscular function in patients with diverse demyelinating disorders. We recently demonstrated that local, transdermal or injectable forms of 4-AP improve myelination, nerve conduction velocity, muscle atrophy, and motor function after traumatic peripheral nerve injury in mice. While oral 4-AP is most commonly used in the clinic, it is unknown whether human equivalent oral doses of 4-AP have effects on traumatic peripheral nerve injury differentiation, myelination, muscle atrophy, functional recovery, and post-injury inflammatory processes in animals. Mice with sciatic nerve crush or denervation injury received oral or intraperitoneal 4-AP(10 μg) or vehicle alone and were examined for pharmacokinetics, motor function, muscle mass, intrinsic muscle force, nerve morphological and gene expression profiles. 4-AP showed linear pharmacokinetics and the maximum plasma 4-AP concentrations were proportional to 4-AP dose. Acute single dose of oral 4-AP administration induced a rapid transient improvement in motor function that was different in traumatic peripheral nerve injury with or without nerve continuity, chronic daily oral 4-AP treatment significantly enhanced post crush injury motor function recovery and this effect was associated with improved myelination, muscle mass, and ex vivo muscle force. Polymerase chain reaction array analysis with crushed nerve revealed significant alterations in gene involved in axonal inflammation and regeneration. These findings provide convincing evidence that regardless of the route of administration, 4-AP can acutely differentiate traumatic peripheral nerve injury with or without nerve continuity and can enhance in vivo functional recovery with better preservation of myelin sheaths, muscle mass, and muscle force. The animal experiments were approved by the University Committee on Animal Research(UCAR) at the University of Rochester(UCAR-2009-019) on March 31, 2017.
基金supported by grants from the National Institutes of Health,USA(No.K08 AR060164-01A)Department of Defense,USA(Nos.W81XWH-16-1-0725 and W81XWH-19-1-0773)in addition to institutional support from the Pennsylvania State University College of Medicine。
文摘We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.
基金supported by the Innovation Program for Highlevel Talents of Guizhou Province (No. 2016-5657)the University of Hull for support。
文摘The binding interactions between 4-aminopyridine(4-AP) and a series of cucurbit[n]urils(Q[5], Q[6],TMe Q[6], Q[7], Q[8]) have been studied using1H NMR spectroscopy, UV–vis absorption spectroscopy,isothermal titration calorimetry(ITC) and X-ray crystallography. The data indicates that the Q[5]@4-AP complex exhibits exo binding, which is not observed in the other four host-guest complexes. Furthermore,X-ray crystallography clearly reveals how the Q[n]s bind with 4-AP to form complexes, for example Q[5]forms an outer-surface complex, whilst Q[6], TMe Q[6] and Q[7] formed 1:1 host and guest type complexes, and Q[8] formed a stable 1:2 ternary complex due to its large cavity, which can accommodate two 4-AP molecules.
基金thegrantsfromtheAdvanceDepartment FoundationfromtheMedicalMinistryofShanghai China! (No 1995 Ⅲ 0 0 8)
文摘Objective To research the direct electrophysiological evidence of discomplete spinal cord injury (SCI) and the effect of 4-aminopyridine on it.Methods Motor evoked potentials (MEPs), both spinal cord recorded MEPs (scMEPs) and extracellularly recorded MEPs (exMEPs) were recorded and characterized on a T13 epidural electrode (scMEPs) and an extracellular microelectrode (exMEPs) for 10 normal rats and 40 rats with lesions of various severity (sham, 35?g*cm force (gcf), 70?gcf, 100?gcf impact injury) at the T8-T9 cord using the Allen's drop model. The incline plane and Tarlov techniques were used to assess clinical neurological function. Results MEPs in the normal rats were elicited by applying transcortical suprathreshold stimulation consisting of 3-4 early negative peaks (N1, N2, N3 and N4) followed by several late waves. The N1 and N2 peaks were largest in the anterior and ventrolateral funiculus, respectively, which was indicative of extrapyramidal pathways. The 100?gcf impact injuries and the cord transection abolished the MEP distal to the lesion, whereas the 35?gcf injuries resulted in a latency shift and amplitude decrement of the MEP peaks. Eighteen of the 20 rats with 70?gcf injuries showed clinical paraplegia. Among them, 7 rats had neurophysiological evidence of residual conduction pathways through the lesioned cord segment, such as the presence of N1 and N2 peaks in the scMEPs or exMEPs. After 4-aminopyridine (4-AP) administrations (1?mg/kg), the amplitude of the spared exMEP increased significantly and spread more widely. Conclusions MEPs evoked by transcortical stimulation travel mostly in the extrapyramidal tract. MEP monitoring could provide an excellent method of detecting the functional integrity of the motor tracts after SCI, and could even detect spared motor fibers after discomplete SCI. Furthermore, the use of 4-AP or other K+ channel blocking agents may be a potential treatment for patients with chronic moderate to severe SCI.
基金the Natural Science Found Council of China (Nos. 20671011, 20331010, 90406002 and 90406024) the Key Laboratory of Structural Chemistry Foundation (No. 060017)
文摘A three-dimensional complex [Cu（3-ampy）（HEO）4]（SO4）·（H2O） （3-ampy = 3-amino- pyridine） has been synthesized. Crystallographic data： C5H16CuN2O9S, Mr = 343.80, triclinic, space group P1, a = 7.675（2）, b = 8.225（3）, c = 10.845（3）A, α= 86.996（4）, β = 76.292（4）, γ= 68.890（4）°, V = 620.0（3）A^3, Z = 2, Dc = 1.841 g/cm^3, F（000） = 354 and μ = 1.971 mm^-1. The structure was refined to R = 0.0269 and wR = 0.0659 for 1838 observed reflections （I 〉 2a（/））. The structure consists of [Cu（3-ampy）（H2O）4]^2＋ cations, SO4^2- anions and lattice water molecules. 3-Ampy acting as a bidentate bridging ligand generates a 1D covalent chain. A supramolecular 2D framework is formed through π-π stacking of pyridine rings. The lattice water molecules and SO4^2- anions are located between the adjacent 2D frameworks. The hydrogen bonding interactions from lattice water molecules and SO4^2- anions to coordinate water extend the 2D framework into a 3D network.
基金supported by the National Natural Science Foundation of China,Nos.82271444(to JP),82271268(to BZ),and 82001346(to YL)the National Key Research and Development Program of China,No.2022YFE0210100(to BZ)。
文摘Parkinson's disease is primarily caused by the loss of dopaminergic neurons in the substantia nigra compacta.Ferroptosis,a novel form of regulated cell death characterized by iron accumulation and lipid peroxidation,plays a vital role in the death of dopaminergic neurons.However,the molecular mechanisms underlying ferroptosis in dopaminergic neurons have not yet been completely elucidated.NADPH oxidase 4 is related to oxidative stress,however,whether it regulates dopaminergic neuronal ferroptosis remains unknown.The aim of this study was to determine whether NADPH oxidase 4 is involved in dopaminergic neuronal ferroptosis,and if so,by what mechanism.We found that the transcriptional regulator activating transcription factor 3 increased NADPH oxidase 4 expression in dopaminergic neurons and astrocytes in an 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced Parkinson's disease model.NADPH oxidase 4 inhibition improved the behavioral impairments observed in the Parkinson's disease model animals and reduced the death of dopaminergic neurons.Moreover,NADPH oxidase 4 inhibition reduced lipid peroxidation and iron accumulation in the substantia nigra of the Parkinson's disease model animals.Mechanistically,we found that NADPH oxidase 4 interacted with activated protein kinase Cαto prevent ferroptosis of dopaminergic neurons.Furthermore,by lowering the astrocytic lipocalin-2 expression,NADPH oxidase 4 inhibition reduced 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-induced neuroinflammation.These findings demonstrate that NADPH oxidase 4 promotes ferroptosis of dopaminergic neurons and neuroinflammation,which contribute to dopaminergic neuron death,suggesting that NADPH oxidase 4 is a possible therapeutic target for Parkinson's disease.
基金supported by a grant from the French Multiple Sclerosis Society(ARSEP,Grant Number:R20163LL)(to AMG)。
文摘Multiple sclerosis(MS)is the most common chronic disease of the central nervous system(CNS)in young adults and represents the first cause of severe handicap,originally non-traumatic(Oh et al.,2018).MS is chara cterized by the infiltration of auto reactive lymphocytes specific to myelin through the blood-brain barrier,which results in the appearance of inflammatory demyelinating lesions caused by the death of the central nervous system myelinating cells,oligodendrocytes(Oh et al.,2018).There is a prevalence sexual with a ratio of three times more affected women than men.
文摘Geometry optimization of p-C_(6)H_(4)-connected cyclo[20]carbon(p-C_(6)H_(4)-C_(20))was carried out at M062X/6-311G(d,p)level,three kinds of bond orders(Mayer,Laplacian,and Wiberg),electron-hole distributions,localized orbital locators(LOL),and infrared(IR)spectrum were also performed at the same level.Based on TD-DFT M062X/6-311G(d,p)method,the first 20 excited states and ultraviolet(UV)spectra of p-C_(6)H_(4)-C_(20) were calculated.Calculation results of π-electron delocalization analyses prove thatπ-electron delocalization of p-C_(6)H_(4)-C_(20) is more likely to occur on shorter C-C bonds rather than longer C-C bonds,and inside/outside of the ring plane rather than above/below the ring plane.Two absorption peaks of p-C_(6)H_(4)-C_(20) locate at about 319 nm and 236 nm,respectively.
文摘Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.
