Overexpression of fibroblast growth factor 13 ameliorates amyloid-β-induced neuronal damage

Previous studies have shown that fibroblast growth factor 13 is downregulated in the brain of both Alzheimer’s disease mouse models and patients,and that it plays a vital role in the learning and memory.However,the underlying mechanisms of fibroblast growth factor 13 in Alzheimer’s disease remain unclear.In this study,we established rat models of Alzheimer’s disease by stereotaxic injection of amyloid-β(Aβ_(1-42))-induced into bilateral hippocampus.We also injected lentivirus containing fibroblast growth factor 13 into bilateral hippocampus to overexpress fibroblast growth factor 13.The expression of fibroblast growth factor 13 was downregulated in the brain of the Alzheimer’s disease model rats.After overexpression of fibroblast growth factor 13,learning and memory abilities of the Alzheimer’s disease model rats were remarkably improved.Fibroblast growth factor 13 overexpression increased brain expression levels of oxidative stress-related markers glutathione,superoxide dismutase,phosphatidylinositol-3-kinase,AKT and glycogen synthase kinase 3β,and anti-apoptotic factor BCL.Furthermore,fibroblast growth factor 13 overexpression decreased the number of apoptotic cells,expression of pro-apoptotic factor BAX,cleaved-caspase 3 and amyloid-βexpression,and levels of tau phosphorylation,malondialdehyde,reactive oxygen species and acetylcholinesterase in the brain of Alzheimer’s disease model rats.The changes were reversed by the phosphatidylinositol-3-kinase inhibitor LY294002.These findings suggest that overexpression of fibroblast growth factor 13 improved neuronal damage in a rat model of Alzheimer’s disease through activation of the phosphatidylinositol-3-kinase/AKT/glycogen synthase kinase 3βsignaling pathway.

Pre-B-cell colony-enhancing factor as a target for protecting against apoptotic neuronal death and mitochondrial damage in ischemia

Focal ischemic stroke（FIS）results from the lack of blood flow in a particular region of the brain and accounts for about 80%of all human strokes.Although tremendous efforts have been made in translational research,the treatment strategies are still limited.Tissue plasminogen activator is the only FDA-approved drug currently available for acute stroke treatment,

“Standby” EMT and “immune cell trapping” structure as novel mechanisms for limiting neuronal damage after CNS injury

The central nervous system （CNS） contains the two most important organs, the brain and spinal cord, for the orchestration of the mental and physical activities of life. Because of its importance, the human body has evolved barrier systems to protect CNS tissue from the external environment. This barrier is a membrane composed of tightly apposed cells and is selectively permeable to specific molecules by way of membrane transporters.

Do new neurons contribute to functional reorganization after brain damage?

The finding that adult neurogenesis occurs constitutively in the brain was a breakthrough in neuroscience and soon gained attention as a possible mechanism for neurorepair after brain damage. In a recent study we show that the dentate gyrus （DG） reorganizes anatomically over neurons undergo maturation time after damage, while new and activate in response to a contextual fear memory recall （Aguilar-Arredondo and Zepeda, 2018）. These findings provide new evidence on the possible role of neurogenesis in cognitive recovery after brain injury.

Autophagy occurs within an hour of adenosine triphosphate treatment after nerve cell damage:the neuroprotective effects of adenosine triphosphate against apoptosis

After hypoxia, ischemia, or inflammatory injuries to the central nervous system, the damaged cells release a large amount of adenosine triphosphate, which may cause secondary neuronal death. Autophagy is a form of cell death that also has neuroprotective effects. Cell Counting Kit assay, monodansylcadaverine staining, flow cytometry, western blotting, and real-time PCR were used to determine the effects of exogenous adenosine triphosphate treatment at different concentrations （2, 4, 6, 8, 10 mmol/L） over time （1, 2, 3, and 6 hours） on the apoptosis and autophagy of SH-SY5Y cells. High concentrations of extracellular adenosine triphosphate induced autophagy and apoptosis of SH-SYSY cells. The enhanced autophagy first appeared, and peaked at 1 hour after treatment with adenosine triphosphate. Cell apoptosis peaked at 3 hours, and persisted through 6 hours. With prolonged exposure to the adenosine triphosphate treatment, the fraction of apoptotic cells increased. These data suggest that the SH-SY5Y neural cells initiated autophagy against apoptosis within an hour of adenosine triphosphate treatment to protect themselves against injury.

Neuronal injury and tumor necrosis factor-alpha immunoreactivity in the rat hippocampus in the early period of asphyxia-induced cardiac arrest under normothermia

Low survival rate occurs in patients who initially experience a spontaneous return of circulation after cardiac arrest（CA）. In this study, we induced asphyxial CA in adult male Sprague-Daley rats, maintained their body temperature at 37 ± 0.5°C, and then observed the survival rate during the post-resuscitation phase. We examined neuronal damage in the hippocampus using cresyl violet（CV） and Fluore-Jade B（F-J B） staining, and pro-inflammatory response using ionized calcium-binding adapter molecule 1（Iba-1）, glial fibrillary acidic protein（GFAP）, and tumor necrosis factor-alpha（TNF-α） immunohistochemistry in the hippocampus after asphyxial CA in rats under normothermia. Our results show that the survival rate decreased gradually post-CA（about 63% at 6 hours, 37% at 1 day, and 8% at 2 days post-CA）. Rats were sacrificed at these points in time post-CA, and no neuronal damage was found in the hippocampus until 1 day post-CA. However, some neurons in the stratum pyramidale of the CA region in the hippocampus were dead 2 days post-CA. Iba-1 immunoreactive microglia in the CA1 region did not change until 1 day postCA, and they were activated（enlarged cell bodies with short and thicken processes） in all layers 2 days postCA. Meanwhile, GFAP-immunoreactive astrocytes did not change significantly until 2 days post-CA. TNF-α immunoreactivity decreased significantly in neurons of the stratum pyramidale in the CA1 region 6 hours post-CA, decreased gradually until 1 day post-CA, and increased significantly again 2 days post-CA. These findings suggest that low survival rate of normothermic rats in the early period of asphyxia-induced CA is related to increased TNF-α immunoreactivity, but not to neuronal damage in the hippocampal CA1 region.

Five percent CO_(2) inhalation alleviates hippocampal glutamate and water homeostasis disturbance,neuronal damage,and learning-memory impairment in sleep-deprived rats

Background:Sleep deprivation causes hippocampal injury,manifesting as neuronal damage and learning-memory impairment.These negative effects may be associated with disturbance of hippocampal glutamate and water homeostasis,which induces excessive neuronal excitability.Five percent CO_(2) inhalation has been shown to suppress neuronal excitability.Here,we aimed to investigate whether 5%CO_(2) inhalation facilitates the recovery of hippocampal glutamate and water homeostasis,neuron morphology,and learning-memory ability in sleep-deprived rats.Methods:Thirty-six Sprague-Dawley female rats were randomly divided into three groups including normal sleep(Group 1,NS,n=12),sleep deprivation followed by sleep recovery(Group 2,SD+SR,n=12),sleep deprivation followed by sleep recovery and 5%CO_(2) inhalation(Group 3,SD+SR+CO_(2),n=12)by random number table.Each group was divided into two subgroups(n=6 each subgroup)for different experiments randomly by random number table.Results:We found that 5%CO_(2) inhalation facilitated the recovery of hippocampal glutamate concentration(7.549±0.310,8.716±0.463,and 7.493±0.281 mmol/L at Days 1,3,and 5 in Group 3,F 2,15=22.06,p<0.0001)and hippocampal apparent diffusion coefficient mean value(8.210±0.274,7.685±0.171,8.265±0.269 at Days 1,3,and 5 in Group 3,F 2,15=10.45,p=0.0014),enhanced expression level of astrocyte-specific membrane protein glutamate transporter-1,promoted the polarized distribution of aquaporin 4,reduced hippocampal neuronal damage and improved learning-memory ability in sleep-deprived rats.Conclusion:This study showed that 5%CO_(2) inhalation can serve as a novel strategy for alleviating sleep deprivation-induced hippocampal injury.

Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage

SIRT6 is a NAD＊-dependent histone deacetylase and has been implicated in the regulation of genomic stability, DNA repair, metabolic homeostasis and several diseases. The effect of SIRT6 in cerebral ischemia and oxygen/glucose deprivation （OGD） has been reported, however the role of SIRT6 in oxidative stress damage remains unclear. Here we used SH-SY5Y neuronal cells and found that overexpression of SIRT6 led to decreased cell viability and increased necrotic cell death and reactive oxygen species （ROS） production under oxidative stress. Mechanistic study revealed that SlRT6 induced autophagy via attenuation of AKT signaling and treatment with autophagy inhibitor 3-MA or knockdown of autophagy-related protein Atg5 rescued HzO2-induced neuronal injury. Conversely, SIRT6 inhibition suppressed autophagy and reduced oxidative stressinduced neuronal damage. These results suggest that SIRT6 might be a potential therapeutic target for neuroprotection.

Critical involvement of lysyl oxidase in seizure-induced neuronal damage through ERK-Alox5-dependent ferroptosis and its therapeutic implications

Recent insights collectively suggest the important roles of lysyl oxidase(LysOX)in the pathological processes of several acute and chronic neurological diseases,but the molecular regulatory mechanisms remain elusive.Herein,we explore the regulatory role of LysOX in the seizure-induced ferroptotic cell death of neurons.Mechanistically,LysOX promotes ferroptosis-associated lipid peroxidation in neurons via activating extracellular regulated protein kinase(ERK)-dependent 5-lipoxygenase(Alox5)signaling.In addition,overexpression of LysOX via adeno-associated viral vector(AAV)-based gene transfer enhances ferroptosis sensitivity and aggravates seizure-induced hippocampal damage.Our studies show that pharmacological inhibition of LysOX withβ-aminopropionitrile(BAPN)significantly blocks seizure-induced ferroptosis and thereby alleviates neuronal damage,while the BAPN-associated cardiotoxicity and neurotoxicity could further be reduced through encapsulation with bioresponsive amorphous calcium carbonate-based nanocarriers.These findings unveil a previously unrecognized LysOX-ERK-Alox5 pathway for ferroptosis regulation during seizure-induced neuronal damage.Suppressing this pathway may yield therapeutic implications for restoring seizure-induced neuronal injury.

Flavonoids from Scutellaria baicalensis Georgi are effective to treat cerebral ischemia/reperfusion

Based on previous studies that have shown flavonoids from the stems and leaves of Scutellaria baicalensis Georgi are neuroprotective agents in a naturally senile, D-galactose, aging in vivo model, as well as an in vitro model of oxidative/hypoxic injury, we established a cerebral ischemia/reperfusion model in rats by middle cerebral artery occlusion. The light/electron microscopic observations found significant neuropathological changes including neuron loss or swelling and rough endoplasmic reticulum injury. Moreover, the activities of lactate dehydrogenase Na＋-K＋-ATPase, Ca2＋-ATPase and superoxide dismutase were significantly lowered, and the levels of malonaldehyde increased. In addition, the memory of rats worsened. However, treatment with flavonoids from Scutellaria baicalensis Georgi （35, 70 and 140 mg/kg） for 13 days dramatically improved the above abnormal changes. These results suggest that the ability of flavonoids from Scutellaria baicalensis Georgi in attenuating cerebral functional and morphological consequences after cerebral ischemia/reperfusion may be beneficial for the treatment of ischemic brain disease.

Polyphenols as potential enhancers of stem cell therapy against neurodegeneration

The potential of polyphenols for treating chronic-degenerative diseases(particularly neurodegenerative diseases)is attractive.However,the selection of the best polyphenol for each treatment,the mechanisms by which they act,and their efficacy are frequently discussed.In this review,the basics and the advances in the field,as well as suggestions for using natural and synthetic polyphenols alone or in a combinatorial strategy with stem cell assays,are compiled and discussed.Thus,stem cells exhibit several responses when polyphenols are added to their environment,which could provide us with knowledge for advancing the elucidation of the origin of neurodegeneration.But also,polyphenols are being included in the innovative strategies of novel therapies for treating neurodegenerative diseases as well as metabolic diseases related to neurodegeneration.In this regard,flavonoid compounds are suggested as the best natural polyphenols due to their several mechanisms for acting in ameliorative effects;but increasing reports are involving other polyphenols.Even if some facts limiting bioactivity prevent them from conventional use,some natural polyphenols and derivatives hold the promise for being improved compounds,judged by their induced effects.The current results suggest polyphenols as enhancers of stem cell therapy against the targeted diseases.

Nerve root magnetic stimulation regulates the synaptic plasticity of injured spinal cord by ascending sensory pathway

Promoting synaptic plasticity and inducing functional reorganization of residual nerve fibers hold clinical significance for restoring motor function following spinal cord injury.Neuromagnetic stimulation targeting the nerve roots has been shown to improve motor function by enhancing nerve conduction in the injured spinal cord and restoring the synaptic ultrastructure of both the sensory and motor cortex.However,our understanding of the neurophysiological mechanisms by which nerve root magnetic stimulation facilitates motor function recovery in the spinal cord is limited,and its role in neuroplasticity remains unclear.In this study,we established a model of spinal cord injury in adult male Sprague–Dawley rats by applying moderate compression at the T10 vertebra.We then performed magnetic stimulation on the L5 nerve root for 3 weeks,beginning on day 3 post-injury.At day 22 post-injury,we observed that nerve root magnetic stimulation downregulated the level of interleukin-6 in the injured spinal cord tissue of rats.Additionally,this treatment reduced neuronal damage and glial scar formation,and increased the number of neurons in the injured spinal cord.Furthermore,nerve root magnetic stimulation decreased the levels of acetylcholine,norepinephrine,and dopamine,and increased the expression of synaptic plasticity-related m RNA and proteins PSD95,GAP43,and Synapsin II.Taken together,these results showed that nerve root magnetic stimulation alleviated neuronal damage in the injured spinal cord,regulated synaptic plasticity,and suppressed inflammatory responses.These findings provide laboratory evidence for the clinical application of nerve root magnetic stimulation in the treatment of spinal cord injury.

Two-step emulsification for the fabrication of homogeneous PCL microspheres encapsulating geniposidic acid with antioxidant properties

The mortality rate of neurological disorders is increasing globally,and natural antioxidant geniposidic acid(GPA)holds great potential in the treatment of neuronal oxidative damage.Nevertheless,its inherent instability constrains its pragmatic utilization.Herein,we introduced a drug delivery system capable of protecting unstable natural active compounds from degradation.Among the various methods for preparing drug-loaded microspheres,the emulsification-solvent evaporation technique is one of the most commonly employed due to its efficiency and simplicity.Nevertheless,this method results in microspheres with heterogeneous particle sizes.To address this limitation,we developed a two-step emulsification method involving stirring and homogenization.Using the biocompatible,synthetic,biodegradable polymer polycaprolactone(PCL)as the drug delivery carrier,we prepared GPA-loaded PCL microspheres via the two-step emulsification method.The results demonstrated that the microspheres possessed uniform particle size(polydispersity index=0.12),excellent drug loading capacity(∼4.86%),sustained drug release profiles(∼68.55%in 264 h),and biocompatibility(cell viability>85%).The in vitro tests showed that the microspheres exerted antioxidant effects by scavenging reactive oxygen species(ROS)induced by oxidative stress,thereby protecting neuronal cells from oxidative damage.This work presents a promising new approach for the treatment of neuronal oxidative damage.

Duplicate preconditioning with sevoflurane in vitro improves neuroprotection in rat brain via activating the extracellular signal-regulated protein kinase

Objective Sevoflurane preconditioning has been demonstrated to reduce cerebral ischemia–reperfusion（IR） injury,but the underlying mechanisms have not been fully elucidated.Besides,different protocols would usually lead to different results.The objective of this study was to determine whether dual exposure to sevoflurane improves the effect of anesthetic preconditioning against oxygen and glucose deprivation（OGD）injury in vitro.Methods Rat hippocampal slices under normoxic conditions（95%O2/5%CO2）were pre-exposed to sevoflurane 1,2 and 3 minimum alveolar concentration （MAC）for 30 min,once or twice,with 15-min washout after each exposure.The slices were then subjected to 13-min OGD treatment（95%N2/5%CO2,glucose-free）,followed by 30-min reoxygenation.The population spikes（PSs）were recorded in the CA1 region of rat hippocampus.The percentage of PS amplitude at the end of 30-min reoxygenation to that before OGD treatment was calculated,since it could indicate the recovery degree of neuronal function.In addition,to assess the role of mitogen-activated protein kinases（MAPKs）in preconditioning,U0126,an inhibitor of extracellular signal–regulated protein kinase（MEK-ERK1/2,ERK1/2 MAPK）,and SB203580,an inhibitor of p38 MAPK,were separately added 10 min before sevoflurane exposure.Results Preconditioning once with sevoflurane 1,2,and 3 MAC increased the percentage of PS amplitude at the end of 30-min reoxygenation to that before OGD treatment,from（15.13±3.79）%（control）to（31.88±5.36）%, （44.00±5.01）%,and（49.50±6.25）%,respectively,and twice preconditioning with sevoflurane 1,2,and 3 MAC increased the percentage to（38.53±4.36）%,（50.74±7.05）%and（55.86±6.23）%,respectively.The effect of duplicate preconditioning with sevoflurane 3 MAC was blocked by U0126[（16.23±4.62）%].Conclusion Sevoflurane preconditioning can induce neuroprotection against OGD injury in vitro,and preconditioning twice enhances this effect.Besides,the activation of extracellular signal–regulated protein kinase（MEK-ERK1/2,ERK1/2 MAPK）may be involved in this process.