Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rode...Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.展开更多
The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration.Axons and dendrites,sometimes referred to as neurites,are extensions of a neuron's cellular body that are...The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration.Axons and dendrites,sometimes referred to as neurites,are extensions of a neuron's cellular body that are used to start networks.Here we explored the effects of diethyl(3,4-dihydroxyphenethylamino)(quinolin-4-yl)methylphosphonate(DDQ)on neurite developmental features in HT22 neuronal cells.In this work,we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22cells expressing mutant Tau(mTau)cDNA.To investigate DDQ chara cteristics,cell viability,biochemical,molecular,western blotting,and immunocytochemistry were used.Neurite outgrowth is evaluated through the segmentation and measurement of neural processes.These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth.These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22.DDQ-treated mTau-HT22 cells(HT22 cells transfected with cDNA mutant Tau)were seen to display increased levels of synaptophysin,MAP-2,andβ-tubulin.Additionally,we confirmed and noted reduced levels of both total and p-Tau,as well as elevated levels of microtubule-associated protein 2,β-tubulin,synaptophysin,vesicular acetylcholine transporter,and the mitochondrial biogenesis protein-pe roxisome prolife rator-activated receptor-gamma coactivator-1α.In mTa u-expressed HT22 neurons,we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth.Our findings conclude that mTa u-HT22(Alzheimer's disease)cells treated with DDQ have functional neurite developmental chara cteristics.The key finding is that,in mTa u-HT22 cells,DDQ preserves neuronal structure and may even enhance nerve development function with mTa u inhibition.展开更多
Objective As the core unit of the limbic system,the hippocampus is involved in the regulation of higher neural activity by integrating emotional encoding and memory storage functions.In the pathological process of epi...Objective As the core unit of the limbic system,the hippocampus is involved in the regulation of higher neural activity by integrating emotional encoding and memory storage functions.In the pathological process of epilepsy,structural remodeling and functional disorders in this region have become the focus of research,and the existing evidence mostly focuses on hippocampal sclerosis,a typical neurodegenerative change.However,there is still a lack of systematic analysis of the pathological subtypes under the International League Against Epilepsy(ILAE)classification system in cross-scale molecular events such as epigenetic regulation and microbiome-brain axis.By integrating clinical cohort data and experimental model evidence,this article focuses on the association characteristics between hippocampal sclerosis subtypes and seizure patterns,and reveals the formation of abnormal hippocampal network and the cascading effect of abnormal hippocampus-related neurotransmitters in the formation of epileptogenic network.The study found that specific pathological subtypes showed a significant correspondence with seizure frequency and drug sensitivity,suggesting that hippocampal sclerosis drives epilepsy progression through multidimensional molecular events.In the future,it is necessary to combine spatial transcriptome and targeted metabolomics technology to analyze the cell interaction network in the hippocampal microenvironment,so as to provide a theoretical basis for the development of subtype-specific antiepileptic strategies.展开更多
Background:Epilepsy is a disease characterized by unprovoked seizures,and it affects around 70 million people worldwide.Standard treatment is ineffective in one third of all epilepsy patients.Temporal Lobe Epilepsy wi...Background:Epilepsy is a disease characterized by unprovoked seizures,and it affects around 70 million people worldwide.Standard treatment is ineffective in one third of all epilepsy patients.Temporal Lobe Epilepsy with Hippocampal Sclerosis(TLE-HS)is the most drug-resistant form of epilepsy,and it also impacts physical,mental,and psychological well-being of patients.Carum carvi extract has demonstrated anti-convulsant,anti-depressant,and anxiolytic properties.This study was designed to investigate if Carum carvi extract can alleviate depression and memory loss symptoms in a TLE-HS animal model.Methods:Male Sprague Dawley rats were used to create a model of TLE-HS and Carum carvi extract treatment,along with appropriate controls,was used to test the efficacy of this herbal extract in reducing the symptoms of depression and memory loss.Results:Forced swim test showed that Carum carvi extract treated TLE-HS rats resulted in significant improvement of the symptoms of depression.However,novel object recognition test showed that memory improvement did not occur.Conclusion:Depression significantly impacts the quality of life in TLE-HS patients,and this study has shown that Carum carvi extract should be explored further as an adjuvant treatment for TLE-HS patients to improve their quality of life.展开更多
BACKGROUND Increasing evidence has shown that hippocampal damage serves as a marker of early cognitive decline in patients with type 2 diabetes mellitus(T2DM);however,the association between hippocampal subregion volu...BACKGROUND Increasing evidence has shown that hippocampal damage serves as a marker of early cognitive decline in patients with type 2 diabetes mellitus(T2DM);however,the association between hippocampal subregion volume changes and cognitive decline in different dimensions remains unclear.AIM To investigate changes in hippocampal subregion volumes in patients with T2DM and their relationship with cognitive function impairment.METHODS Sixty patients with T2DM and 32 healthy controls were recruited.All participants underwent a 3.0 T magnetic resonance scan and a series of clinical assessments.Hippocampal subfield volumes were determined using FreeSurfer 7.4.1.A two-sample t-test was used to evaluate group differences.Partial correlation analysis was performed to assess the relationship between hippocampal subregion volumes and cognitive function.aP<0.05 was considered statistically significant.RESULTS Compared with controls,the volume of right hippocampus-amygdala transition area(t=-3.053,P=0.003)in patients with T2DM was significantly reduced,which was negatively correlated with the required time of the Trail Making Test(TMT)-A(r=-0.331,P=0.028)and TMT-B(r=-0.402,P=0.007)and positively correlated with the scores of Symbol Digit Modalities Test(r=0.381,P=0.011),Auditory Verbal Learning Test(AVLT)-N7(r=0.309,P=0.041),and Digital Span Test(r=0.300,P=0.048).The volume of the right molecular layer(t=-2.998,P=0.004)was also significantly reduced,which was positively associated with the scores of AVLT-N7(r=0.311,P=0.045).In addition,the left hippocampal fissure volume(t=3.617,P=0.002)was significantly increased in patients with T2DM.CONCLUSION Declines in cognitive performance,especially memory and executive function,are linked to changes in the volumes of the right hippocampus-amygdala transition area and right molecular layer in patients with T2DM.展开更多
Dear Editor,The importance of the medial entorhinal cortex(MEC)for memory and spatial navigation has been shown repeatedly in many species,including mice and humans[1,2].It is,therefore,not surprising that the connect...Dear Editor,The importance of the medial entorhinal cortex(MEC)for memory and spatial navigation has been shown repeatedly in many species,including mice and humans[1,2].It is,therefore,not surprising that the connectivity of this structure has been studied extensively over the past century,mainly using a range of anterograde and retrograde anatomical tracers[3].展开更多
DDeeaarr EEddiittoorr,,The encoding and retrieval of emotional memories demands intricate interplay within the limbic network,where the network state is subject to significant reconfiguration by learning-induced plast...DDeeaarr EEddiittoorr,,The encoding and retrieval of emotional memories demands intricate interplay within the limbic network,where the network state is subject to significant reconfiguration by learning-induced plasticity,behavioral state,and contextual information[1].展开更多
Growth arrest DNA damage-inducible protein 45β(GADD45B)has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related ps...Growth arrest DNA damage-inducible protein 45β(GADD45B)has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related psychopathological processes.However,its precise role and mechanism of action in stress susceptibility remain elusive.In this study,we found a significant reduction in GADD45B expression specifically in the ventral,but not the dorsal hippocampal CA1(dCA1)of stress-susceptible mice.Furthermore,we demonstrated that GADD45B negatively regulates susceptibility to social stress and NMDA receptor-dependent long-term potentiation(LTP)in the ventral hippocampal CA1(vCA1).Importantly,through pharmacological inhibition using the NMDA receptor antagonist MK801,we provided further evidence supporting the hypothesis that GADD45B potentially modulates susceptibility to social stress by influencing NMDA receptor-mediated LTP.Collectively,these results suggested that modulation of NMDA receptor-mediated synaptic plasticity is a pivotal mechanism underlying the regulation of susceptibility to social stress by GADD45B.展开更多
Objective The entorhino-hippocampal pathway is the major excitatory input from neurons of the entorhinal cortex on both ipsilateral and contralateral hippocampus/dentate gyrus. This fiber tract consists of the alvear ...Objective The entorhino-hippocampal pathway is the major excitatory input from neurons of the entorhinal cortex on both ipsilateral and contralateral hippocampus/dentate gyrus. This fiber tract consists of the alvear path, the perforant path and a crossed commissural projection. In this study, the histogenesis and development of the various subsets of the entorhino-hippocampal projection have been investigated. Methods Dil, DiO and fast blue tracing as well as anti-calretinin immunocytochemistry were carried out with prenatal and postnatal rats at different ages. Results The alvear path and the commissural pathway started to develop as early as embryonic day （E） 16, while the first perforant afferents reached the stratum lacunosum-moleculare of the hippocampus at E 17 and the outer molecular layer of dentate gyrus at postnatal day （P） 2, respectively. Retrograde tracing with DiI identified entorhinal neurons in layer II to IV as the origin of entorhino-hippocampal pathway. Furthermore, anti-calretinin immunocytochemistry revealed transitory Cajal- Retzius （CR） cells in the stratum lacunosum-moleculare of the hippocampus from as early as E 16. DiI labeling of entorhinal cortex fibers and combined calretinin-immunocytochemistry showed a close association between CR cells and entorhinal afferents. Conclusion The subsets of entorhino-hippocampal pathway appear in the developmental hippocampus during El6 - P2. The temporal and spatial relationship between CR cell and perforant afferent suggests the role of this cell type as a guiding cue for entorhinal afferents at early cortical development.展开更多
Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammal...Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammals,including humans.These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory.Importantly,studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases.Alzheimer’s disease(AD)is one of the most common forms of dementia affecting millions of people.Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus.Therefore,there has been growing interest in identifying how hippocampal neurogenesis is affected in AD.However,the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood.In this review,we summarized the recent literature on AHN and its impairments in AD.展开更多
Objective To examine the effect of acetylcholine（ACh）on the electric activities of pain-excitation neurons （PEN）and pain-inhibitation neurons（PIN）in the hippocampal CA1 area of normal rats or morphinistic rats,a...Objective To examine the effect of acetylcholine（ACh）on the electric activities of pain-excitation neurons （PEN）and pain-inhibitation neurons（PIN）in the hippocampal CA1 area of normal rats or morphinistic rats,and to explore the role of ACh in regulation of pain perception in CA1 area under normal condition and morphine addiction.Methods The trains of electric impulses applied to sciatic nerve were set as noxious stimulation.The discharges of PEN and PIN in the CA l area were recorded extracellularly by glass microelectrode.We observed the influence of intracerebroventricular （i.c.v.）injection of ACh and atropine on the noxious stimulation-evoked activities of PEN and PIN in the CA1 area.Results Noxious stimulation enhanced the electric activity of PEN and depressed that of PIN in the CA1 area of both normal and addiction rats.In normal rats,ACh decrease the pain-evoked discharge frequency of PEN,while increased the frequency of PIN.These effects reached the peak value at 4 min after injection of ACh.In morphinistic rats,ACh also inhibited the PEN electric activity and potentialized the PIN electric activity,but the maximum effect appeared at 6 min after administration. The ACh-induced responses were significantly blocked by muscarinic receptor antagonist atropine.Conclusion Cholinergic neurons and muscarinic receptors in the hippocampal CA1 area are involved in the processing of nociceptive information and they may play an analgesia role in pain modulation.Morphine addiction attenuated the sensitivity of painrelated neurons to the noxious information.展开更多
Icariin(ICA) has a significant capacity to protect against depression and hippocampal injury,but it cannot effectively cross the bloodbrain barrier and accumulate in the brain.Therefore,the mechanism by which ICA prot...Icariin(ICA) has a significant capacity to protect against depression and hippocampal injury,but it cannot effectively cross the bloodbrain barrier and accumulate in the brain.Therefore,the mechanism by which ICA protects against hippocampal injury in depression remains unclear.In this study,we performed proteomics analysis of cerebrospinal fluid to investigate the mechanism by which ICA prevents dysfunctional hippocampal neurogenesis in depression.A rat model of depression was established through exposure to chronic unpredictable mild stress for 6 weeks,after which 120 mg/kg ICA was administered subcutaneously every day.The results showed that ICA alleviated depressive symptoms,learning and memory dysfunction,dysfunctional neurogenesis,and neuronal loss in the dentate gyrus of rats with depression.Neural stem cells from rat embryonic hippocampi were cultured in media containing 20% cerebrospinal fluid from each group of rats and then treated with 100 μM corticosterone.The addition of cerebrospinal fluid from rats treated with ICA largely prevented the corticosterone-mediated inhibition of neuronal proliferation and differentiation.Fifty-two differentially expressed proteins regulated by chronic unpredictable mild stress and ICA were identified through proteomics analysis of cerebrospinal fluid.These proteins were mainly involved in the ribosome,PI3 K-Akt signaling,and interleukin-17 signaling pathways.Parallel reaction monitoring mass spectrometry showed that Rps4 x,Rps12,Rps14,Rps19,Hsp90 b1,and Hsp90 aa1 were up-regulated by chronic unpredictable mild stress and down-regulated by ICA.In contrast,Htr A1 was down-regulated by chronic unpredictable mild stress and up-regulated by ICA.These findings suggest that ICA can prevent depression and dysfunctional hippocampal neurogenesis through regulating the expression of certain proteins found in the cerebrospinal fluid.The study was approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2017.展开更多
Ginsenoside Rb1 has been reported to exert anti-aging and anti-neurodegenerative effects. In the present study, we investigate whether ginsenoside Rb1 is involved in neurite outgrowth and neuroprotection against damag...Ginsenoside Rb1 has been reported to exert anti-aging and anti-neurodegenerative effects. In the present study, we investigate whether ginsenoside Rb1 is involved in neurite outgrowth and neuroprotection against damage induced by amyloid beta（25–35） in cultured hippocampal neurons, and explore the underlying mechanisms. Ginsenoside Rb1 significantly increased neurite outgrowth in hippocampal neurons, and increased the expression of phosphorylated-Akt and phosphorylated extracellular signal-regulated kinase 1/2. These effects were abrogated by API-2 and PD98059, inhibitors of the signaling proteins Akt and MEK. Additionally, cultured hippocampal neurons were exposed to amyloid beta（25–35） for 30 minutes; ginsenoside Rb1 prevented apoptosis induced by amyloid beta（25–35）, and this effect was blocked by API-2 and PD98059. Furthermore, ginsenoside Rb1 significantly reversed the reduction in phosphorylated-Akt and phosphorylated extracellular signal-regulated kinase 1/2 levels induced by amyloid beta（25–35）, and API-2 neutralized the effect of ginsenoside Rb1. The present results indicate that ginsenoside Rb1 enhances neurite outgrowth and protects against neurotoxicity induced by amyloid beta（25–35） via a mechanism involving Akt and extracellular signal-regulated kinase 1/2 signaling.展开更多
Ginsenoside Rg1（Rg1） has anti-aging and anti-neurodegenerative effects. However, the mechanisms underlying these actions remain unclear. The aim of the present study was to determine whether Rg1 affects hippocampal ...Ginsenoside Rg1（Rg1） has anti-aging and anti-neurodegenerative effects. However, the mechanisms underlying these actions remain unclear. The aim of the present study was to determine whether Rg1 affects hippocampal survival and neurite outgrowth in vitro after exposure to amyloid-beta peptide fragment 25–35（Aβ_（25–35））, and to explore whether the extracellular signal-regulated kinase（ERK） and Akt signaling pathways are involved in these biological processes. We cultured hippocampal neurons from newborn rats for 24 hours, then added Rg1 to the medium for another 24 hours, with or without pharmacological inhibitors of the mitogen-activated protein kinase（MAPK） family or Akt signaling pathways for a further 24 hours. We then immunostained the neurons for growth associated protein-43, and measured neurite length. In a separate experiment, we exposed cultured hippocampal neurons to Aβ_（25–35） for 30 minutes, before adding Rg1 for 48 hours, with or without Akt or MAPK inhibitors, and assessed neuronal survival using Hoechst 33258 staining, and phosphorylation of ERK1/2 and Akt by western blot analysis. Rg1 induced neurite outgrowth, and this effect was blocked by API-2（Akt inhibitor） and PD98059（MAPK/ERK kinase inhibitor）, but not by SP600125 or SB203580（inhibitors of c-Jun N-terminal kinase and p38 MAPK, respectively）. Consistent with this effect, Rg1 upregulated the phosphorylation of Akt and ERK1/2; these effects were reversed by API-2 and PD98059, respectively. In addition, Rg1 significantly reversed Aβ_（25–35）-induced apoptosis; this effect was blocked by API-2 and PD98059, but not by SP600125 or SB203580. Finally, Rg1 significantly reversed the Aβ_（25–35）-induced decrease in Akt and ERK1/2 phosphorylation, but API-2 prevented this reversal. Our results indicate that Rg1 enhances neurite outgrowth and protects against Aβ_（25–35）-induced damage, and that its mechanism may involve the activation of Akt and ERK1/2 signaling.展开更多
BACKGROUND：Chloride channels participate in non-neuronal apoptosis.However,it remains unclear whether chloride channels are involved in ischemic neuronal apoptosis.OBJECTIVE：To explore the effects of 4-acetamido-4＇...BACKGROUND：Chloride channels participate in non-neuronal apoptosis.However,it remains unclear whether chloride channels are involved in ischemic neuronal apoptosis.OBJECTIVE：To explore the effects of 4-acetamido-4＇-isothiocyanatostilbene-2,2＇-disulfonic acid （SITS） and 4,4＇-diisothiocyanostilbene-2,2＇-disulfonic acid （DIDS）,two chloride channel blockers,on the hippocampal neuronal apoptosis induced by 3-morpholinosydnonimine （SIN-1） based on the nitric oxide toxicity theory of neuronal apoptosis following ischemic brain injury.DESIGN,TIME AND SETTING：Comparative observation and in vitro experiments were performed at the laboratory of Zhuhai Campus of Zunyi Medical College from January to May 2009.MATERIALS：SIN-1,SITS,and DIDS were purchased from Sigma,USA.METHODS：Hippocampal neurons from Sprague-Dawley rats,aged 1 day,were cultured In vitro for 12 days and randomly assigned to control,SIN-1,or chloride channel blocker groups.SIN-1 group neurons were induced by SIN-1 for 18 hours to establish a model of ischemic neuronal apoptosis.Neurons in chloride channel blocker groups were treated with SITS or DIDS plus SIN-1 for 18 hours.The controls were cultured in DMEM/Ham＇s F12 complete medium alone.MAIN OUTCOME MEASURES：The apoptotic neurons and nuclear appearance were detected by Hoechst 33258 fluorescence staining; neuronal viability was quantitatively determined by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide analysis.Caspase-3 activity was analyzed by Western blot.RESULTS：SIN-1 （1 mmol/L） dramatically induced apoptosis （50%-60%）.SITS and DIDS inhibited nitric oxide-induced neuronal injury in a dose-dependent manner,suppressed caspase-3 activation,reduced neuronal apoptosis,and improved neuronal survival.CONCLUSION：Chloride channel blockers can protect against neuronal injury induced by NO.Chloride channels might be involved in neuronal apoptosis following cerebral ischemia.展开更多
Glucagon-like peptide-1 receptor has anti-apoptotic,anti-inflammatory,and neuroprotective effects.It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory...Glucagon-like peptide-1 receptor has anti-apoptotic,anti-inflammatory,and neuroprotective effects.It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses;however,it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms.We explored the effects of glucagon-like peptide-1 receptor on nociception,cognition,and neuroinflammation in chronic pain.A rat model of chronic pain was established using left L5 spinal nerve ligation.The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation.Electrophysiological examinations showed that,after treatment with exendin-4,paw withdrawal frequency of the left limb was significantly reduced,and pain was relieved.In addition,in the Morris water maze test,escape latency increased and the time to reach the platform decreased following exendin-4 treatment.Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus,as well as an increase in the expression of tumor necrosis factor alpha,interleukin 1 beta,and interleukin 6.All of these effects could be reversed by exendin-4 treatment.These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China(approval No.WDRM 20171214)on September 22,2017.展开更多
Hypoxic injuries during fetal distress have been shown to cause reduced expression of micro RNA-27a（mi R-27a）,which regulates sensitivity of cortical neurons to apoptosis.We hypothesized that miR-27 a overexpression...Hypoxic injuries during fetal distress have been shown to cause reduced expression of micro RNA-27a（mi R-27a）,which regulates sensitivity of cortical neurons to apoptosis.We hypothesized that miR-27 a overexpression attenuates hypoxia- and ischemia-induced neuronal apoptosis by regulating FOXO1,an important transcription factor for regulating the oxidative stress response.miR-27 a mimic was transfected into hippocampal neurons to overexpress miR-27 a.Results showed increased hippocampal neuronal viability and decreased caspase-3 expression.The luciferase reporter gene system demonstrated that mi R-27 a directly binded to FOXO1 3′UTR in hippocampal neurons and inhibited FOXO1 expression,suggesting that FOXO1 was the target gene for mi R-27 a.These findings confirm that mi R-27 a protects hippocampal neurons against oxygen-glucose deprivation-induced injuries.The mechanism might be mediated by modulation of FOXO1 and apoptosis-related gene caspase-3 expression.展开更多
Previous studies have shown that chrysophanol protects against learning and memory impairments in lead-exposed adult mice. In the present study, we investigated whether chrysophanol can alleviate learning and memory d...Previous studies have shown that chrysophanol protects against learning and memory impairments in lead-exposed adult mice. In the present study, we investigated whether chrysophanol can alleviate learning and memory dysfunction and hippocampal neuronal injury in lead-exposed neonatal mice. At the end of lactation, chrysophanol（0.1, 1.0, 10.0 mg/kg） was administered to the neonatal mice by intraperitoneal injection for 15 days. Chrysophanol significantly alleviated injury to hippocampal neurons and improved learning and memory abilities in the lead-poisoned neonatal mice. Chrysophanol also significantly decreased lead content in blood, brain, heart, spleen, liver and kidney in the lead-exposed neonatal mice. The levels of malondialdehyde in the brain, liver and kidney were significantly reduced, and superoxide dismutase and glutathione peroxidase activities were significantly increased after chrysophanol treatment. Collectively, these findings indicate that chrysophanol can significantly reduce damage to hippocampal neurons in lead-exposed neonatal mice.展开更多
Ilexonin A is a compound isolated from the root of Ilex pubescens,a traditional Chinese medicine.Ilexonin A has been shown to play a neuroprotective role by regulating the activation of astrocytes and microglia in the...Ilexonin A is a compound isolated from the root of Ilex pubescens,a traditional Chinese medicine.Ilexonin A has been shown to play a neuroprotective role by regulating the activation of astrocytes and microglia in the peri-infarct area after ischemia.However,the effects of ilexonin A on astrocytes and microglia in the infarct-free region of the hippocampal CA1 region remain unclear.Focal cerebral ischemia models were established by 2-hour occlusion of the middle cerebral artery in rats.Ilexonin A(20,40 or 80 mg/kg)was administered immediately after ischemia/reperfusion.The astrocyte marker glial fibrillary acidic protein,microglia marker Iba-1,neural stem cell marker nestin and inflammation markers were detected by immunohistochemistry and western blot assay.Expression levels of tumor necrosis factor-αand interleukin 1βwere determined by enzyme linked immunosorbent assay in the hippocampal CA1 tissue.Astrocytes were activated immediately in progressively increasing numbers from 1,3,to 7 days post-ischemia/reperfusion.The number of activated astrocytes further increased in the hippocampal CA1 region after treatment with ilexonin A.Microglial cells remained quiescent after ischemia/reperfusion,but became activated after treatment with ilexonin A.Ilexonin A enhanced nestin expression and reduced the expression of tumor necrosis factor-αand interleukin 1βin the hippocampus post-ischemia/reperfusion.The results of the present study suggest that ilexonin A has a neuroprotective effect in the hippocampus after ischemia/reperfusion,probably through regulating astrocytes and microglia activation,promoting neuronal stem cell proliferation and reducing the levels of pro-inflammatory factors.This study was approved by the Animal Ethics Committee of the Fujian Medical University Union Hospital,China.展开更多
N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the bra...N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the brain. Previous studies have paid little attention to the role of the N-methyl-D-aspartate receptor subunit 1 (NR1) in neurogenesis in the hippocampus of schizophrenia. A mouse model of schizophrenia was established by intraperitoneal injection of 0.6 mg/kg MK-801, once a day, for 14 days. In N-methyl-D-aspartate-treated mice, N-methyl-D-aspartate was administered by intracerebroventricular injection in schizophrenia mice on day 15. The number of NR1-, Ki67- or BrdU-immunoreactive cells in the dentate gyrus was measured by immunofluorescence staining. Our data showed the number of NR1-immunoreactive cells increased along with the decreasing numbers of BrdU- and Ki67-immunoreactive cells in the schizophrenia groups compared with the control group. N-methyl-D-aspartate could reverse the above changes. These results indicated that NR1 can regulate neurogenesis in the hippocampal dentate gyrus of schizophrenia mice, supporting NR1 as a promising therapeutic target in the treatment of schizophrenia. This study was approved by the Experimental Animal Ethics Committee of the Ningxia Medical University, China (approval No. 2014-014) on March 6, 2014.展开更多
基金supported by the National Institutes of Health,Nos.AA025919,AA025919-03S1,and AA025919-05S1(all to RAF).
文摘Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease.
基金supported by NIH grants AG079264(to PHR)and AG071560(to APR)。
文摘The process of neurite outgrowth and branching is a crucial aspect of neuronal development and regeneration.Axons and dendrites,sometimes referred to as neurites,are extensions of a neuron's cellular body that are used to start networks.Here we explored the effects of diethyl(3,4-dihydroxyphenethylamino)(quinolin-4-yl)methylphosphonate(DDQ)on neurite developmental features in HT22 neuronal cells.In this work,we examined the protective effects of DDQ on neuronal processes and synaptic outgrowth in differentiated HT22cells expressing mutant Tau(mTau)cDNA.To investigate DDQ chara cteristics,cell viability,biochemical,molecular,western blotting,and immunocytochemistry were used.Neurite outgrowth is evaluated through the segmentation and measurement of neural processes.These neural processes can be seen and measured with a fluorescence microscope by manually tracing and measuring the length of the neurite growth.These neuronal processes can be observed and quantified with a fluorescent microscope by manually tracing and measuring the length of the neuronal HT22.DDQ-treated mTau-HT22 cells(HT22 cells transfected with cDNA mutant Tau)were seen to display increased levels of synaptophysin,MAP-2,andβ-tubulin.Additionally,we confirmed and noted reduced levels of both total and p-Tau,as well as elevated levels of microtubule-associated protein 2,β-tubulin,synaptophysin,vesicular acetylcholine transporter,and the mitochondrial biogenesis protein-pe roxisome prolife rator-activated receptor-gamma coactivator-1α.In mTa u-expressed HT22 neurons,we observed DDQ enhanced the neurite characteristics and improved neurite development through increased synaptic outgrowth.Our findings conclude that mTa u-HT22(Alzheimer's disease)cells treated with DDQ have functional neurite developmental chara cteristics.The key finding is that,in mTa u-HT22 cells,DDQ preserves neuronal structure and may even enhance nerve development function with mTa u inhibition.
文摘Objective As the core unit of the limbic system,the hippocampus is involved in the regulation of higher neural activity by integrating emotional encoding and memory storage functions.In the pathological process of epilepsy,structural remodeling and functional disorders in this region have become the focus of research,and the existing evidence mostly focuses on hippocampal sclerosis,a typical neurodegenerative change.However,there is still a lack of systematic analysis of the pathological subtypes under the International League Against Epilepsy(ILAE)classification system in cross-scale molecular events such as epigenetic regulation and microbiome-brain axis.By integrating clinical cohort data and experimental model evidence,this article focuses on the association characteristics between hippocampal sclerosis subtypes and seizure patterns,and reveals the formation of abnormal hippocampal network and the cascading effect of abnormal hippocampus-related neurotransmitters in the formation of epileptogenic network.The study found that specific pathological subtypes showed a significant correspondence with seizure frequency and drug sensitivity,suggesting that hippocampal sclerosis drives epilepsy progression through multidimensional molecular events.In the future,it is necessary to combine spatial transcriptome and targeted metabolomics technology to analyze the cell interaction network in the hippocampal microenvironment,so as to provide a theoretical basis for the development of subtype-specific antiepileptic strategies.
基金supported by the URC Aga Khan University(Project ID:212003)Pakistan Science Foundation(Project Code:710110-201-20001-500-53413-0000).
文摘Background:Epilepsy is a disease characterized by unprovoked seizures,and it affects around 70 million people worldwide.Standard treatment is ineffective in one third of all epilepsy patients.Temporal Lobe Epilepsy with Hippocampal Sclerosis(TLE-HS)is the most drug-resistant form of epilepsy,and it also impacts physical,mental,and psychological well-being of patients.Carum carvi extract has demonstrated anti-convulsant,anti-depressant,and anxiolytic properties.This study was designed to investigate if Carum carvi extract can alleviate depression and memory loss symptoms in a TLE-HS animal model.Methods:Male Sprague Dawley rats were used to create a model of TLE-HS and Carum carvi extract treatment,along with appropriate controls,was used to test the efficacy of this herbal extract in reducing the symptoms of depression and memory loss.Results:Forced swim test showed that Carum carvi extract treated TLE-HS rats resulted in significant improvement of the symptoms of depression.However,novel object recognition test showed that memory improvement did not occur.Conclusion:Depression significantly impacts the quality of life in TLE-HS patients,and this study has shown that Carum carvi extract should be explored further as an adjuvant treatment for TLE-HS patients to improve their quality of life.
基金Supported by the Bethune Charitable Foundation,No.Z04JKM2022E035the Liyang City's 2023 Annual research and development Plan Follows Nanjing Project,No.LC2024001.
文摘BACKGROUND Increasing evidence has shown that hippocampal damage serves as a marker of early cognitive decline in patients with type 2 diabetes mellitus(T2DM);however,the association between hippocampal subregion volume changes and cognitive decline in different dimensions remains unclear.AIM To investigate changes in hippocampal subregion volumes in patients with T2DM and their relationship with cognitive function impairment.METHODS Sixty patients with T2DM and 32 healthy controls were recruited.All participants underwent a 3.0 T magnetic resonance scan and a series of clinical assessments.Hippocampal subfield volumes were determined using FreeSurfer 7.4.1.A two-sample t-test was used to evaluate group differences.Partial correlation analysis was performed to assess the relationship between hippocampal subregion volumes and cognitive function.aP<0.05 was considered statistically significant.RESULTS Compared with controls,the volume of right hippocampus-amygdala transition area(t=-3.053,P=0.003)in patients with T2DM was significantly reduced,which was negatively correlated with the required time of the Trail Making Test(TMT)-A(r=-0.331,P=0.028)and TMT-B(r=-0.402,P=0.007)and positively correlated with the scores of Symbol Digit Modalities Test(r=0.381,P=0.011),Auditory Verbal Learning Test(AVLT)-N7(r=0.309,P=0.041),and Digital Span Test(r=0.300,P=0.048).The volume of the right molecular layer(t=-2.998,P=0.004)was also significantly reduced,which was positively associated with the scores of AVLT-N7(r=0.311,P=0.045).In addition,the left hippocampal fissure volume(t=3.617,P=0.002)was significantly increased in patients with T2DM.CONCLUSION Declines in cognitive performance,especially memory and executive function,are linked to changes in the volumes of the right hippocampus-amygdala transition area and right molecular layer in patients with T2DM.
文摘Dear Editor,The importance of the medial entorhinal cortex(MEC)for memory and spatial navigation has been shown repeatedly in many species,including mice and humans[1,2].It is,therefore,not surprising that the connectivity of this structure has been studied extensively over the past century,mainly using a range of anterograde and retrograde anatomical tracers[3].
基金supported by the National Natural Science Foundation of China(T2394531)the National Key R&D Program of China(2024YFF1206500)+1 种基金the Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)ZJ Lab,and the Shanghai Center for Brain Science and Brain-Inspired Technology,China.
文摘DDeeaarr EEddiittoorr,,The encoding and retrieval of emotional memories demands intricate interplay within the limbic network,where the network state is subject to significant reconfiguration by learning-induced plasticity,behavioral state,and contextual information[1].
基金supported by the National Natural Science Foundation of China(82201667,82371195,and 82304474)the Research Fund of Jianghan University(2023JCYJ15).
文摘Growth arrest DNA damage-inducible protein 45β(GADD45B)has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related psychopathological processes.However,its precise role and mechanism of action in stress susceptibility remain elusive.In this study,we found a significant reduction in GADD45B expression specifically in the ventral,but not the dorsal hippocampal CA1(dCA1)of stress-susceptible mice.Furthermore,we demonstrated that GADD45B negatively regulates susceptibility to social stress and NMDA receptor-dependent long-term potentiation(LTP)in the ventral hippocampal CA1(vCA1).Importantly,through pharmacological inhibition using the NMDA receptor antagonist MK801,we provided further evidence supporting the hypothesis that GADD45B potentially modulates susceptibility to social stress by influencing NMDA receptor-mediated LTP.Collectively,these results suggested that modulation of NMDA receptor-mediated synaptic plasticity is a pivotal mechanism underlying the regulation of susceptibility to social stress by GADD45B.
文摘Objective The entorhino-hippocampal pathway is the major excitatory input from neurons of the entorhinal cortex on both ipsilateral and contralateral hippocampus/dentate gyrus. This fiber tract consists of the alvear path, the perforant path and a crossed commissural projection. In this study, the histogenesis and development of the various subsets of the entorhino-hippocampal projection have been investigated. Methods Dil, DiO and fast blue tracing as well as anti-calretinin immunocytochemistry were carried out with prenatal and postnatal rats at different ages. Results The alvear path and the commissural pathway started to develop as early as embryonic day （E） 16, while the first perforant afferents reached the stratum lacunosum-moleculare of the hippocampus at E 17 and the outer molecular layer of dentate gyrus at postnatal day （P） 2, respectively. Retrograde tracing with DiI identified entorhinal neurons in layer II to IV as the origin of entorhino-hippocampal pathway. Furthermore, anti-calretinin immunocytochemistry revealed transitory Cajal- Retzius （CR） cells in the stratum lacunosum-moleculare of the hippocampus from as early as E 16. DiI labeling of entorhinal cortex fibers and combined calretinin-immunocytochemistry showed a close association between CR cells and entorhinal afferents. Conclusion The subsets of entorhino-hippocampal pathway appear in the developmental hippocampus during El6 - P2. The temporal and spatial relationship between CR cell and perforant afferent suggests the role of this cell type as a guiding cue for entorhinal afferents at early cortical development.
基金supported by the Medical Scientist Training Program(T32 GM008444)Mechanistic Study of Declining Hippocampal Neurogenesis in the Aging Brain(R01AG066912 to S.G.)。
文摘Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain.Recent evidence suggests that adult hippocampal neurogenesis(AHN)persists throughout life in mammals,including humans.These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory.Importantly,studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases.Alzheimer’s disease(AD)is one of the most common forms of dementia affecting millions of people.Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus.Therefore,there has been growing interest in identifying how hippocampal neurogenesis is affected in AD.However,the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood.In this review,we summarized the recent literature on AHN and its impairments in AD.
基金the National Natural Science Foundation of China（No.30240058）.
文摘Objective To examine the effect of acetylcholine（ACh）on the electric activities of pain-excitation neurons （PEN）and pain-inhibitation neurons（PIN）in the hippocampal CA1 area of normal rats or morphinistic rats,and to explore the role of ACh in regulation of pain perception in CA1 area under normal condition and morphine addiction.Methods The trains of electric impulses applied to sciatic nerve were set as noxious stimulation.The discharges of PEN and PIN in the CA l area were recorded extracellularly by glass microelectrode.We observed the influence of intracerebroventricular （i.c.v.）injection of ACh and atropine on the noxious stimulation-evoked activities of PEN and PIN in the CA1 area.Results Noxious stimulation enhanced the electric activity of PEN and depressed that of PIN in the CA1 area of both normal and addiction rats.In normal rats,ACh decrease the pain-evoked discharge frequency of PEN,while increased the frequency of PIN.These effects reached the peak value at 4 min after injection of ACh.In morphinistic rats,ACh also inhibited the PEN electric activity and potentialized the PIN electric activity,but the maximum effect appeared at 6 min after administration. The ACh-induced responses were significantly blocked by muscarinic receptor antagonist atropine.Conclusion Cholinergic neurons and muscarinic receptors in the hippocampal CA1 area are involved in the processing of nociceptive information and they may play an analgesia role in pain modulation.Morphine addiction attenuated the sensitivity of painrelated neurons to the noxious information.
基金supported by the National Natural Science Foundation of China,No.81774102 (to LLW)。
文摘Icariin(ICA) has a significant capacity to protect against depression and hippocampal injury,but it cannot effectively cross the bloodbrain barrier and accumulate in the brain.Therefore,the mechanism by which ICA protects against hippocampal injury in depression remains unclear.In this study,we performed proteomics analysis of cerebrospinal fluid to investigate the mechanism by which ICA prevents dysfunctional hippocampal neurogenesis in depression.A rat model of depression was established through exposure to chronic unpredictable mild stress for 6 weeks,after which 120 mg/kg ICA was administered subcutaneously every day.The results showed that ICA alleviated depressive symptoms,learning and memory dysfunction,dysfunctional neurogenesis,and neuronal loss in the dentate gyrus of rats with depression.Neural stem cells from rat embryonic hippocampi were cultured in media containing 20% cerebrospinal fluid from each group of rats and then treated with 100 μM corticosterone.The addition of cerebrospinal fluid from rats treated with ICA largely prevented the corticosterone-mediated inhibition of neuronal proliferation and differentiation.Fifty-two differentially expressed proteins regulated by chronic unpredictable mild stress and ICA were identified through proteomics analysis of cerebrospinal fluid.These proteins were mainly involved in the ribosome,PI3 K-Akt signaling,and interleukin-17 signaling pathways.Parallel reaction monitoring mass spectrometry showed that Rps4 x,Rps12,Rps14,Rps19,Hsp90 b1,and Hsp90 aa1 were up-regulated by chronic unpredictable mild stress and down-regulated by ICA.In contrast,Htr A1 was down-regulated by chronic unpredictable mild stress and up-regulated by ICA.These findings suggest that ICA can prevent depression and dysfunctional hippocampal neurogenesis through regulating the expression of certain proteins found in the cerebrospinal fluid.The study was approved by the Experimental Animal Ethics Committee of Guangzhou University of Chinese Medicine of China in March 2017.
基金supported by grants from the National Natural Science Foundation of China,No.30971531,81070987
文摘Ginsenoside Rb1 has been reported to exert anti-aging and anti-neurodegenerative effects. In the present study, we investigate whether ginsenoside Rb1 is involved in neurite outgrowth and neuroprotection against damage induced by amyloid beta（25–35） in cultured hippocampal neurons, and explore the underlying mechanisms. Ginsenoside Rb1 significantly increased neurite outgrowth in hippocampal neurons, and increased the expression of phosphorylated-Akt and phosphorylated extracellular signal-regulated kinase 1/2. These effects were abrogated by API-2 and PD98059, inhibitors of the signaling proteins Akt and MEK. Additionally, cultured hippocampal neurons were exposed to amyloid beta（25–35） for 30 minutes; ginsenoside Rb1 prevented apoptosis induced by amyloid beta（25–35）, and this effect was blocked by API-2 and PD98059. Furthermore, ginsenoside Rb1 significantly reversed the reduction in phosphorylated-Akt and phosphorylated extracellular signal-regulated kinase 1/2 levels induced by amyloid beta（25–35）, and API-2 neutralized the effect of ginsenoside Rb1. The present results indicate that ginsenoside Rb1 enhances neurite outgrowth and protects against neurotoxicity induced by amyloid beta（25–35） via a mechanism involving Akt and extracellular signal-regulated kinase 1/2 signaling.
基金financially supported by the National Program on Key Basic Research Project of China(973 Program),No.2010CB945600,2011CB965100the National Natural Science Foundation of China,No.81070987,30971531,81371213a grant from the International Science & Technology Collaboration Program,No.2011DF30010
文摘Ginsenoside Rg1（Rg1） has anti-aging and anti-neurodegenerative effects. However, the mechanisms underlying these actions remain unclear. The aim of the present study was to determine whether Rg1 affects hippocampal survival and neurite outgrowth in vitro after exposure to amyloid-beta peptide fragment 25–35（Aβ_（25–35））, and to explore whether the extracellular signal-regulated kinase（ERK） and Akt signaling pathways are involved in these biological processes. We cultured hippocampal neurons from newborn rats for 24 hours, then added Rg1 to the medium for another 24 hours, with or without pharmacological inhibitors of the mitogen-activated protein kinase（MAPK） family or Akt signaling pathways for a further 24 hours. We then immunostained the neurons for growth associated protein-43, and measured neurite length. In a separate experiment, we exposed cultured hippocampal neurons to Aβ_（25–35） for 30 minutes, before adding Rg1 for 48 hours, with or without Akt or MAPK inhibitors, and assessed neuronal survival using Hoechst 33258 staining, and phosphorylation of ERK1/2 and Akt by western blot analysis. Rg1 induced neurite outgrowth, and this effect was blocked by API-2（Akt inhibitor） and PD98059（MAPK/ERK kinase inhibitor）, but not by SP600125 or SB203580（inhibitors of c-Jun N-terminal kinase and p38 MAPK, respectively）. Consistent with this effect, Rg1 upregulated the phosphorylation of Akt and ERK1/2; these effects were reversed by API-2 and PD98059, respectively. In addition, Rg1 significantly reversed Aβ_（25–35）-induced apoptosis; this effect was blocked by API-2 and PD98059, but not by SP600125 or SB203580. Finally, Rg1 significantly reversed the Aβ_（25–35）-induced decrease in Akt and ERK1/2 phosphorylation, but API-2 prevented this reversal. Our results indicate that Rg1 enhances neurite outgrowth and protects against Aβ_（25–35）-induced damage, and that its mechanism may involve the activation of Akt and ERK1/2 signaling.
基金the Science and Technology Department of Guizhou Province,No. (2007)2127the Key Development Program of Science and Technology Department of Guizhou Province,No. [2009]3075A Grant from the Science and Technology Department of Zhuhai,No. PC20081010
文摘BACKGROUND：Chloride channels participate in non-neuronal apoptosis.However,it remains unclear whether chloride channels are involved in ischemic neuronal apoptosis.OBJECTIVE：To explore the effects of 4-acetamido-4＇-isothiocyanatostilbene-2,2＇-disulfonic acid （SITS） and 4,4＇-diisothiocyanostilbene-2,2＇-disulfonic acid （DIDS）,two chloride channel blockers,on the hippocampal neuronal apoptosis induced by 3-morpholinosydnonimine （SIN-1） based on the nitric oxide toxicity theory of neuronal apoptosis following ischemic brain injury.DESIGN,TIME AND SETTING：Comparative observation and in vitro experiments were performed at the laboratory of Zhuhai Campus of Zunyi Medical College from January to May 2009.MATERIALS：SIN-1,SITS,and DIDS were purchased from Sigma,USA.METHODS：Hippocampal neurons from Sprague-Dawley rats,aged 1 day,were cultured In vitro for 12 days and randomly assigned to control,SIN-1,or chloride channel blocker groups.SIN-1 group neurons were induced by SIN-1 for 18 hours to establish a model of ischemic neuronal apoptosis.Neurons in chloride channel blocker groups were treated with SITS or DIDS plus SIN-1 for 18 hours.The controls were cultured in DMEM/Ham＇s F12 complete medium alone.MAIN OUTCOME MEASURES：The apoptotic neurons and nuclear appearance were detected by Hoechst 33258 fluorescence staining; neuronal viability was quantitatively determined by 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide analysis.Caspase-3 activity was analyzed by Western blot.RESULTS：SIN-1 （1 mmol/L） dramatically induced apoptosis （50%-60%）.SITS and DIDS inhibited nitric oxide-induced neuronal injury in a dose-dependent manner,suppressed caspase-3 activation,reduced neuronal apoptosis,and improved neuronal survival.CONCLUSION：Chloride channel blockers can protect against neuronal injury induced by NO.Chloride channels might be involved in neuronal apoptosis following cerebral ischemia.
基金supported by the Special Grant for Scientific and Technological Development Conducted by The Central Government of China in 2016:Quality Test and Operation with Anesthesia Center of Experimental Animal of Hubei Province,No.2060403(to BHZ)
文摘Glucagon-like peptide-1 receptor has anti-apoptotic,anti-inflammatory,and neuroprotective effects.It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses;however,it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms.We explored the effects of glucagon-like peptide-1 receptor on nociception,cognition,and neuroinflammation in chronic pain.A rat model of chronic pain was established using left L5 spinal nerve ligation.The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation.Electrophysiological examinations showed that,after treatment with exendin-4,paw withdrawal frequency of the left limb was significantly reduced,and pain was relieved.In addition,in the Morris water maze test,escape latency increased and the time to reach the platform decreased following exendin-4 treatment.Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus,as well as an increase in the expression of tumor necrosis factor alpha,interleukin 1 beta,and interleukin 6.All of these effects could be reversed by exendin-4 treatment.These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China(approval No.WDRM 20171214)on September 22,2017.
基金supported by the National Natural Science Foundation of China,No.81101159the Natural Science Foundation of Jiangsu Province of China,No.BK20151268
文摘Hypoxic injuries during fetal distress have been shown to cause reduced expression of micro RNA-27a（mi R-27a）,which regulates sensitivity of cortical neurons to apoptosis.We hypothesized that miR-27 a overexpression attenuates hypoxia- and ischemia-induced neuronal apoptosis by regulating FOXO1,an important transcription factor for regulating the oxidative stress response.miR-27 a mimic was transfected into hippocampal neurons to overexpress miR-27 a.Results showed increased hippocampal neuronal viability and decreased caspase-3 expression.The luciferase reporter gene system demonstrated that mi R-27 a directly binded to FOXO1 3′UTR in hippocampal neurons and inhibited FOXO1 expression,suggesting that FOXO1 was the target gene for mi R-27 a.These findings confirm that mi R-27 a protects hippocampal neurons against oxygen-glucose deprivation-induced injuries.The mechanism might be mediated by modulation of FOXO1 and apoptosis-related gene caspase-3 expression.
基金financially supported by the Science and Technology Commission Foundation of Zhangjiakou City,No.1021098Dthe Medical Scientific Research Project of Health Bureau of Hebei Province,No.20100144+2 种基金the Natural Science Foundation of Hebei Province,No.H2012405016the Innovative Talents Project of Hebei North University,No.CXRC1325the Major Projects of Hebei North University,No.ZD201310
文摘Previous studies have shown that chrysophanol protects against learning and memory impairments in lead-exposed adult mice. In the present study, we investigated whether chrysophanol can alleviate learning and memory dysfunction and hippocampal neuronal injury in lead-exposed neonatal mice. At the end of lactation, chrysophanol（0.1, 1.0, 10.0 mg/kg） was administered to the neonatal mice by intraperitoneal injection for 15 days. Chrysophanol significantly alleviated injury to hippocampal neurons and improved learning and memory abilities in the lead-poisoned neonatal mice. Chrysophanol also significantly decreased lead content in blood, brain, heart, spleen, liver and kidney in the lead-exposed neonatal mice. The levels of malondialdehyde in the brain, liver and kidney were significantly reduced, and superoxide dismutase and glutathione peroxidase activities were significantly increased after chrysophanol treatment. Collectively, these findings indicate that chrysophanol can significantly reduce damage to hippocampal neurons in lead-exposed neonatal mice.
基金supported by the Natural Science Foundation of Fujian Province of China,No.2014J01327the Program for New Century Excellent Talents in Colleges and Universities of Fujian Province of China,No.NCETFJ-0704the Professorial Academic Development Foundation of Fujian Medical University of China,No.JS09014(all to GYZ)
文摘Ilexonin A is a compound isolated from the root of Ilex pubescens,a traditional Chinese medicine.Ilexonin A has been shown to play a neuroprotective role by regulating the activation of astrocytes and microglia in the peri-infarct area after ischemia.However,the effects of ilexonin A on astrocytes and microglia in the infarct-free region of the hippocampal CA1 region remain unclear.Focal cerebral ischemia models were established by 2-hour occlusion of the middle cerebral artery in rats.Ilexonin A(20,40 or 80 mg/kg)was administered immediately after ischemia/reperfusion.The astrocyte marker glial fibrillary acidic protein,microglia marker Iba-1,neural stem cell marker nestin and inflammation markers were detected by immunohistochemistry and western blot assay.Expression levels of tumor necrosis factor-αand interleukin 1βwere determined by enzyme linked immunosorbent assay in the hippocampal CA1 tissue.Astrocytes were activated immediately in progressively increasing numbers from 1,3,to 7 days post-ischemia/reperfusion.The number of activated astrocytes further increased in the hippocampal CA1 region after treatment with ilexonin A.Microglial cells remained quiescent after ischemia/reperfusion,but became activated after treatment with ilexonin A.Ilexonin A enhanced nestin expression and reduced the expression of tumor necrosis factor-αand interleukin 1βin the hippocampus post-ischemia/reperfusion.The results of the present study suggest that ilexonin A has a neuroprotective effect in the hippocampus after ischemia/reperfusion,probably through regulating astrocytes and microglia activation,promoting neuronal stem cell proliferation and reducing the levels of pro-inflammatory factors.This study was approved by the Animal Ethics Committee of the Fujian Medical University Union Hospital,China.
基金supported by the National Natural Science Foundation of China,No.81160169(to JL),81460214(to JL),31660270(to JD),31460255(to JD)the Natural Science Foundation of Ningxia Hui Autonomous Region of China,No.2018AAC02005(to JL)
文摘N-methyl-D-aspartate receptor hypofunction is the basis of pathophysiology in schizophrenia. Blocking the N-methyl-D-aspartate receptor impairs learning and memory abilities and induces pathological changes in the brain. Previous studies have paid little attention to the role of the N-methyl-D-aspartate receptor subunit 1 (NR1) in neurogenesis in the hippocampus of schizophrenia. A mouse model of schizophrenia was established by intraperitoneal injection of 0.6 mg/kg MK-801, once a day, for 14 days. In N-methyl-D-aspartate-treated mice, N-methyl-D-aspartate was administered by intracerebroventricular injection in schizophrenia mice on day 15. The number of NR1-, Ki67- or BrdU-immunoreactive cells in the dentate gyrus was measured by immunofluorescence staining. Our data showed the number of NR1-immunoreactive cells increased along with the decreasing numbers of BrdU- and Ki67-immunoreactive cells in the schizophrenia groups compared with the control group. N-methyl-D-aspartate could reverse the above changes. These results indicated that NR1 can regulate neurogenesis in the hippocampal dentate gyrus of schizophrenia mice, supporting NR1 as a promising therapeutic target in the treatment of schizophrenia. This study was approved by the Experimental Animal Ethics Committee of the Ningxia Medical University, China (approval No. 2014-014) on March 6, 2014.
