After spinal cord injury,programmed cell death is common.In this context,autophagy plays a crucial role in clearing cellular debris,while necroptosis exacerbates neuroinflammation and further damages neural structures...After spinal cord injury,programmed cell death is common.In this context,autophagy plays a crucial role in clearing cellular debris,while necroptosis exacerbates neuroinflammation and further damages neural structures.The neuroprotective drug davunetide has shown substantial therapeutic effects on brain diseases,but its role in treating spinal cord injury remains unclear.Therefore,the aim of this study was to investigate the effects of davunetide on cell death after spinal cord injury.To do this,we established a mouse model of spinal cord contusion and administered davunetide intranasally daily at a dose of 0.5μg/5μL.Mouse locomotor function was assessed using footprint analysis and Basso Mouse Scale scoring,while the extent of spinal cord injury was evaluated using Masson’s trichrome staining.The expression levels of proteins related to locomotor function and spinal cord injury were analyzed by Western blotting and immunofluorescence staining,and protein-protein interactions were evaluated using immunoprecipitation techniques.Our results demonstrated that davunetide not only reduced the size of the injury area but also promoted the recovery of locomotor function after spinal cord injury.Specifically,davunetide exerted its effects by enhancing autophagy and inhibiting necroptosis.Inhibition of autophagy reversed the protective effects of davunetide on necroptosis.Further investigation revealed that davunetide acted through the SIRT1-FOXO1-TFEB signaling pathway,which is key to its therapeutic effects.These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms.This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury.展开更多
A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment.Davunetide,an active fragment of the activity-...A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment.Davunetide,an active fragment of the activity-dependent neuroprotective protein(ADNP),has been implicated in social and cognitive protection.However,the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood.In this study,ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice.The neuropathological basis was also explored using Golgi staining,morphological analysis,western blotting,electrophysiological analysis,and behavioral analysis.Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane.In adulthood,anterior cingulate cortex(ACC)neurons exposed to sevoflurane exhibited a decrease in dendrite number,total dendrite length,and spine density.Furthermore,the expression levels of Homer,PSD95,synaptophysin,and vglut2 were significantly reduced in the sevoflurane group.Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents(mEPSCs).Notably,davunetide significantly ameliorated the synaptic defects,social behavior deficits,and cognitive impairments induced by sevoflurane.Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca^(2+)activity via the Wnt/β-catenin signaling,resulting in decreased expression of synaptic proteins.Suppression of Wnt signaling was restored in the davunetide-treated group.Thus,ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics.This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.展开更多
基金supported by the Natural Science Foundation of Zhejiang Province,No.LY21H060009(to WN)National Natural Science Foundation of China,Nos.82072192 and 82372540(to KZ)+2 种基金Medical and Health Technology Plan Project of Zhejiang Province,No.2024KY155(to KZ)Natural Science Foundation of Ningbo,No.2023J256(to KZ)Science and Technology Bureau Foundation of Wenzhou,No.Y20220211(to CW).
文摘After spinal cord injury,programmed cell death is common.In this context,autophagy plays a crucial role in clearing cellular debris,while necroptosis exacerbates neuroinflammation and further damages neural structures.The neuroprotective drug davunetide has shown substantial therapeutic effects on brain diseases,but its role in treating spinal cord injury remains unclear.Therefore,the aim of this study was to investigate the effects of davunetide on cell death after spinal cord injury.To do this,we established a mouse model of spinal cord contusion and administered davunetide intranasally daily at a dose of 0.5μg/5μL.Mouse locomotor function was assessed using footprint analysis and Basso Mouse Scale scoring,while the extent of spinal cord injury was evaluated using Masson’s trichrome staining.The expression levels of proteins related to locomotor function and spinal cord injury were analyzed by Western blotting and immunofluorescence staining,and protein-protein interactions were evaluated using immunoprecipitation techniques.Our results demonstrated that davunetide not only reduced the size of the injury area but also promoted the recovery of locomotor function after spinal cord injury.Specifically,davunetide exerted its effects by enhancing autophagy and inhibiting necroptosis.Inhibition of autophagy reversed the protective effects of davunetide on necroptosis.Further investigation revealed that davunetide acted through the SIRT1-FOXO1-TFEB signaling pathway,which is key to its therapeutic effects.These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms.This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury.
基金supported by the National Natural Science Foundation of China(82171170,81971076,82371277 to H.Z.,82101345 to L.R.L.)。
文摘A growing number of studies have demonstrated that repeated exposure to sevoflurane during development results in persistent social abnormalities and cognitive impairment.Davunetide,an active fragment of the activity-dependent neuroprotective protein(ADNP),has been implicated in social and cognitive protection.However,the potential of davunetide to attenuate social deficits following sevoflurane exposure and the underlying developmental mechanisms remain poorly understood.In this study,ribosome and proteome profiles were analyzed to investigate the molecular basis of sevoflurane-induced social deficits in neonatal mice.The neuropathological basis was also explored using Golgi staining,morphological analysis,western blotting,electrophysiological analysis,and behavioral analysis.Results indicated that ADNP was significantly down-regulated following developmental exposure to sevoflurane.In adulthood,anterior cingulate cortex(ACC)neurons exposed to sevoflurane exhibited a decrease in dendrite number,total dendrite length,and spine density.Furthermore,the expression levels of Homer,PSD95,synaptophysin,and vglut2 were significantly reduced in the sevoflurane group.Patch-clamp recordings indicated reductions in both the frequency and amplitude of miniature excitatory postsynaptic currents(mEPSCs).Notably,davunetide significantly ameliorated the synaptic defects,social behavior deficits,and cognitive impairments induced by sevoflurane.Mechanistic analysis revealed that loss of ADNP led to dysregulation of Ca^(2+)activity via the Wnt/β-catenin signaling,resulting in decreased expression of synaptic proteins.Suppression of Wnt signaling was restored in the davunetide-treated group.Thus,ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics.This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved.
