Apoptosis Of Hippocampal Neurons Research Articles

MiR-421 Binds to PINK1 and Enhances Neural Stem Cell Self-Renewal via HDAC3-Dependent FOXO3 Activation.

Dysfunctions of neural stem cells (NSCs) often lead to a variety of neurological diseases. Thus, therapies based on NSCs have gained increasing attention recently. It has been documented that microRNA (miR)-421 represses the autophagy and apoptosis of mouse hippocampal neurons and confers a role in the repair of ischemic brain injury (IBI). Herein, we aimed to illustrate the effects of miR-421 on NSC self-renewal. The downstream factors of miR-421 were predicted initially, followed by gain- and loss-of-function assays to examine their effects on NSC self-renewal. Immunoprecipitation and dual luciferase assays were conducted to validate the interaction among miR-421, PTEN-induced putative kinase 1 (PINK1), HDAC3, and forkhead box O3 (FOXO3). A mouse model with IBI was developed to substantiate the impact of the miR-421/PINK1/HDAC3/FOXO3 axis on NSC self-renewal. The expression of miR-421 was downregulated during differentiation of human embryonic NSCs, and miR-421 overexpression accelerated NSC self-renewal. Besides, miR-421 targeted PINK1 and restricted its expression in NSCs and further suppressed HDAC3 phosphorylation and enhanced FOXO3 acetylation. In conclusion, our data elucidated that miR-421 overexpression may facilitate NSC self-renewal through the PINK1/HDAC3/FOXO3 axis, which may provide potential therapeutic targets for the development of novel therapies for IBI.

Dexmedetomidine Ameliorates Postoperative Cognitive Dysfunction via the MicroRNA-381-Mediated EGR1/p53 Axis.

Postoperative cognitive dysfunction (POCD; cognitive change associated with anesthesia and surgery) is one of the most serious long-term postoperative complications that occur in elderly patients. Dexmedetomidine (DEX) has been shown to be beneficial for improving outcomes of postoperative cognitive function. However, the exact mechanism underlying this role requires is yet to be found. The present study aims to determine the pathways involved in the protective effects of DEX against POCD in C57BL/6J aged mice. DEX was administered after POCD modeling in C57BL/6J aged mice. The cognitive function was evaluated after DEX treatment using novel object recognition, open field, and Y-maze tests. We also assessed its effects on neuron apoptosis and production of TNF-α and IL-1β in mouse brain tissues as well as expression levels of DNA damage-related proteins p53, p21, and γH2AX. Interactions between early growth response 1 (EGR1) and p53, microRNA (miR)-381, and EGR1 were identified by ChIP and luciferase reporter assays, and gain- and loss-of-function experiments were performed to confirm the involvement of their interaction in POCD. DEX administration attenuated hippocampal neuron apoptosis, neuroinflammation, DNA damage, and cognitive impairment in aged mice. miR-381 targeted EGR1 and disrupted its interaction with p53, leading to a decline in hippocampal neuron apoptosis, DNA damage, neuroinflammation, and cognitive impairment. Furthermore, DEX administration resulted in the enhancement of miR-381 expression and the subsequent inhibition of EGR1/p53 to protect against cognitive impairment in aged mice. Overall, these results indicate that DEX may have a potential neuroprotective effect against POCD via the miR-381/EGR1/p53 signaling, shedding light on the mechanisms involved in neuroprotection in POCD.

Febrile Seizure-Related miR-148a-3p Exerts Neuroprotection by Promoting the Proliferation of Hippocampal Neurons in Children with Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) is the most common epilepsy in both adult and children. Some microRNAs (miRNAs) are abnormally expressed in neurological diseases. This study aimed to investigate the expression level and clinical significance of miR-148a-3p in TLE children and explore its effect on the biological viability of hippocampal neurons. The expression level of miR-148a-3p in the serum of TLE children was examined using quantitative real-time PCR. A receiver operating characteristic curve was plotted to determine the diagnostic accuracy of miR-148a-3p in TLE. Hippocampal neurons were cultured in magnesium-free medium to construct a TLE cell model. The effects of miR-148a-3p on hippocampal neuronal viability and apoptosis rate were detected by MTT and flow cytometry, respectively. miR-148a-3p was overexpressed and correlated with seizure frequency and febrile seizure (FS) history in TLE children. miR-148a-3p was of great value in the diagnosis of TLE, and it can be used to distinguish cases with FS history. Hippocampal neurons treated with magnesium-free medium were used as an in vitro model of TLE and showed significantly increased miR-148a-3p, decreased cell viability, and increased cell apoptosis, while these changes were eliminated markedly by miR-148a-3p knockdown. miR-148a-3p is overexpressed and associated with seizure frequency and FS history and serves as a novel diagnostic biomarker in TLE. In addition, the downregulation of miR-148a-3p exerts neuroprotective role by improving hippocampal neuronal cell viability. miR-148a-3p may provide new ideas for the treatment and diagnosis of TLE.

The molecular mechanism underlying mitophagy-mediated hippocampal neuron apoptosis in diabetes-related depression.

Diabetes‐related depression (DD) is a major complication of diabetes mellitus. Our previous studies indicated that glutamate (Glu) and hippocampal neuron apoptosis are key signal and direct factor leading to diabetes‐related depression, respectively. However, the accurate pathogenesis remains to be unclear. We hypothesized that diabetes‐related depression might be associated with the mitophagy‐mediated hippocampal neuron apoptosis, triggered by aberrant Glu‐glutamate receptor2 (GluR2)‐Parkin pathway. To testify this hypothesis, here the rat model of DD in vivo and in vitro were both established so as to uncover the potential mechanism of DD based on mitophagy and apoptosis. We found that DD rats exhibit an elevated glutamate levels followed by monoamine neurotransmitter deficiency and depressive‐like behaviour, and DD modelling promoted autophagosome formation and caused mitochondrial impairment, eventually leading to hippocampal neuron apoptosis via aberrant Glu‐GluR2‐Parkin pathway. Further, in vitro study demonstrated that the simulated DD conditions resulted in an abnormal glutamate and monoamine neurotransmitter levels followed by autophagic flux increment, mitochondrial membrane potential reduction and mitochondrial reactive oxygen species and lactic dehydrogenase elevation. Interestingly, both GluR2 and mammalian target of rapamycin (mTOR) receptor blocker aggravated mitophagy‐induced hippocampal neuron apoptosis and abnormal expression of apoptotic protein. In contrast, both GluR2 and mTOR receptor agonist ameliorated those apoptosis in simulated DD conditions. Our findings revealed that mitophagy‐mediated hippocampal neuron apoptosis, triggered by aberrant Glu‐GluR2‐Parkin pathway, is responsible for depressive‐like behaviour and monoamine neurotransmitter deficiency in DD rats. This work provides promising molecular targets and strategy for the treatment of DD.

RETRACTED: MicroRNA-16-5p/BTG2 axis affects neurological function, autophagy and apoptosis of hippocampal neurons in Alzheimer's disease

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief as there are concerns about the reliability of the results. Concerns have been raised about the western blot bands in Figures 6 B + D having the same eyebrow shaped phenotype as found in many other publications as detailed here (https://pubpeer.com/publications/B32F93859FBAA13471ED0FFCA5BCB6). The journal requested the corresponding author to comment on these concerns and send the raw data, however the author was not able to provide uncropped images of the original gels. The Editor-in-Chief therefore no longer has confidence in the data and conclusions of this study.

Retraction.

Retraction: "Effects of microRNA-129 and its target gene c-Fos on proliferation and apoptosis of hippocampal neurons in rats with epilepsy via the MAPK signaling pathway," by Dong-Mei Wu, Yu-Tong Zhang, Jun Lu, Yuan-Lin Zheng, J Cell Physiol. 2018; 6632-6643: The above article, published online on 30 November 2017 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/10.1002/jcp.26297) has been retracted by agreement between the journal's Editor in Chief, Prof. Dr. Gregg Fields, and Wiley Periodicals LLC. The retraction has been agreed following an investigation based on allegations raised by a third party. Several flaws and inconsistencies between results presented and experimental methods described were found. The editors consider the conclusions of this article to be invalid.

Retraction.

Retraction: "MicroRNA-421 suppresses the apoptosis and autophagy of hippocampal neurons in epilepsy mice model by inhibition of the TLR/MYD88 pathway," by Xin Wen, Xin-Rui Han, Yong-Jian Wang, Shan Wang, Min Shen, Zi-Feng Zhang, Shao-Hua Fan, Qun Shan, Liang Wang, Meng-Qiu Li, Bin Hu, Chun-Hui Sun, Dong-Mei Wu, Jun Lu, Yuan-Lin Zheng, J Cell Physiol. 2018; 7022-7034: The above article, published online on 30 January 2018 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/10.1002/jcp.26498) has been retracted by agreement between the journal's Editor in Chief, Prof. Dr. Gregg Fields, and Wiley Periodicals LLC. The retraction has been agreed following an investigation based on allegations raised by a third party. A detailed investigation revealed that several image elements of the experimental data were published elsewhere in a different scientific context. Thus, the editors consider the conclusions of this article to be invalid.

Retraction.

Retraction: "Effects of microRNA-10a on synapse remodeling in hippocampal neurons and neuronal cell proliferation and apoptosis through the BDNF-TrkB signaling pathway in a rat model of Alzheimer's disease," by Bo-Wen Wu, Mi-Shan Wu, Jin-Dong Guo, J Cell Physiol. 2018; 5281-5292: The above article, published online on 07 December 2017 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/10.1002/jcp.26328) has been retracted by agreement between the journal's Editor in Chief, Prof. Dr. Gregg Fields, and Wiley Periodicals LLC. The retraction has been agreed following an investigation based on allegations raised by a third party. Several flaws and inconsistencies between results presented and experimental methods described were found, the editors consider the conclusions of this article to be invalid.

Methyl-CpG-Binding Domain Protein 3 Promotes Seizures by Recruiting Methyltransferase DNMT1 to Enhance TREM2 Methylation.

Epilepsy represents a hazardous neurological disorder, underpinned by a pathophysiological process that is yet to be fully understood. Here, we aimed to elucidate the effect of methyl-CpG-binding domain protein 3 (MBD3) on hippocampal neuronal damage in epileptic mice by targeting the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. The expression of MBD3 was determined by Western blot in a hippocampal neuronal culture (HNC) epileptic model established using the low Mg2+ECF culture method. The interaction between MBD3 and DNA methyltransferase 1 (DNMT1) was determined via co-immunoprecipitation and mass spectrometry analysis. Bisulfite modification and sequencing was performed to evaluate the degree of methylation of triggering receptor expressed on myeloid cells 2 (TREM2). The viability and apoptosis of hippocampal neurons were detected by CCK-8 and TUNEL assays, respectively. Finally, the effect of MBD3 was verified in vivo. MBD3 was highly expressed in the HNC model of epilepsy, with its interaction with DNMT1 found to promote the hypermethylation of TREM2 at site cg25748868. Additionally, decreased TREM2 and inhibited PI3K/Akt pathway was observed in the HNC epileptic model. Simultaneous inhibition of MBD3 and DNMT1 decreased the methylation level at cg25748868, up-regulated TREM2 expression, and activated the PI3K/Akt pathway, thereby arresting neuronal damage. Inhibition of MBD3 reduced the level of epileptic seizures, down-regulated cg25748868 methylation, activated TREM2-mediated signaling pathways, and alleviated hippocampal neuronal damage in the acute seizure mouse models. The present study unveiled that MBD3 and DNMT1 synergistically enhanced hypermethylation of cg25748868 in TREM2, and promoted the onset of epilepsy via inhibition of the PI3K/Akt pathway.

Geniposide ameliorates chronic unpredictable mild stress induced depression-like behavior through inhibition of ceramide-PP2A signaling via the PI3K/Akt/GSK3β axis.

Depression is a severe mental disorder. Unfortunately, more than half of patients with major depression disorder cannot achieve remission after initial treatment with an antidepressant. Geniposide, a bioactive iridoid glycoside isolated from Gardenia jasminoides Ellis, can ameliorate depressive-like behaviors in mice. However, the underlying mechanism is still not very clear. The pharmacological methods including ELISA, immunofluorescence, and Western blot were used to investigate the role of geniposide on chronic unpredictable mild stress (CUMS)-induced depression mice. In this study, we found that geniposide could inhibit CUMS-induced depressive-like behaviors in mice. Geniposide is able to reduce the levels of ceramide and lower the activity of acid sphingomyelinase (ASM) in hippocampus; besides, ASM inhibitor (amitriptyline) can decrease the concentration of ceramide and ameliorate depressive-like behaviors of mice. Moreover, geniposide can also alleviate CUMS-induced hippocampal neuronal apoptosis and increase the phosphorylated form of PI3K, Akt, and GSK3β. Additionally, PI3K inhibitor (LY294002) can also abolish the neuroprotective effect of geniposide on hippocampal neurons in vitro. These results indicate that geniposide exert a potential antidepressant-like effect on CUMS mice, and its effect might be associated with activated PI3K/Akt/GSK3β signaling, reduced the level of ceramide and hippocampal neuron apoptosis.

MiR-124 protects against cognitive dysfunction induced by sevoflurane anesthesia in vivo and in vitro through targeting calpain small subunit 1 via NF-κB signaling pathway.

Postoperative cognitive dysfunction (POCD) is an impairment of cognition that affects post-surgery patients. Sevoflurane anesthesia is linked to cognitive dysfunction correlated to the expression of miRNA levels. In the current study, we investigated if miR-124 can offer protection against cognitive deficits induced by sevoflurane in a spatial learning paradigm, and examined the molecular mechanisms through cell cultures. Escape latency, platform crossings in probe trials and swimming speed in the Morris water maze in sevoflurane-treated mice were utilized as a measure of cognitive function. The relative miR-124 expression, and mRNA expressions of Bax, caspase-3 and Bcl-2 in sevoflurane-treated hippocampal cultures were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Moreover, the changes in interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α) and IL-6 were determined using enzyme-linked immunosorbent assay (ELISA). The binding between miR-124 and calpain small subunit 1 (Capn4) was verified with site-directed mutagenesis. The involvement of the nuclear factor kappa B (NF-κB) signaling pathway was examined using western blot analysis. Our findings indicated that the miR-124 expression was inhibited by sevoflurane treatment in live rats and mouse hippocampal neurons to prevent apoptosis and inflammatory responses. We confirmed Capn4 as a target of miR-124. Treatment with sevoflurane enhanced the expression of Capn4, while overexpression of miR124 suppressed the enhanced expression of Capn4. Also, miR-124 inhibited apoptosis in murine hippocampal neurons induced by sevoflurane via the NF-κB signaling pathway. Our findings demonstrated that miR-124 exerted its neuroprotective role against sevoflurane via targeting Capn4 and NF-κB signaling pathways. Our work may provide a novel and efficacious treatment for sevoflurane anesthesia-related cognitive dysfunction.

Green tea protects against hippocampal neuronal apoptosis in diabetic encephalopathy by inhibiting JNK/MLCK signaling.

Although diabetic encephalopathy (DE) is a major late complication of diabetes, the pathophysiology of postural instability in DE remains poorly understood. Prior studies have suggested that neuronal apoptosis is closely associated with cognitive function, but the mechanism remains to be elucidated. Green tea, which is a non-fermented tea, contains a number of tea polyphenols, alkaloids, amino acids, polysaccharides and other components. Some studies have found that drinking green tea can reduce the incidence of neurodegenerative diseases and improve cognitive dysfunction. We previously found that myosin light chain kinase (MLCK) regulates apoptosis in high glucose-induced hippocampal neurons. In neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, activation of the JNK signaling pathway promotes neuronal apoptosis. However, the relationship between JNK and MLCK remains to be elucidated. Green tea serum was obtained using seropharmacological methods and applied to hippocampal neurons. In addition, a type 1 diabetes rat model was established and green tea extract was administered, and the Morris water maze test, Cell Counting Kit-8 assays, flow cytometry, western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling assays were used to examine the effects of green tea on hippocampal neuronal apoptosis in diabetic rats. The results demonstrated that green tea can protect against hippocampal neuronal apoptosis by inhibiting the JNK/MLCK pathway and ultimately improves cognitive function in diabetic rats. The present study provided novel insights into the neuroprotective effects of green tea.

Shikonin Attenuates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment by Inhibiting Apoptosis via PTEN/Akt/CREB/BDNF Signaling.

Shikonin (SK) exerts neuroprotective effects; however, to date, its protective effect against chronic cerebral hypoperfusion- (CCH-) induced vascular dementia (VaD) has not been investigated. Therefore, the current study investigated whether SK could mitigate the cognitive deficits caused by CCH. The effects of SK treatment on the PTEN/Akt/CREB/BDNF signaling pathway and apoptosis in hippocampal neurons were examined in a rat model of VaD established via bilateral common carotid artery occlusion (BCCAO). Fifty-two rats were randomly divided into 4 groups: sham, vehicle, SK-L (10 mg/kg SK per day), and SK-H (25 mg/kg SK per day). SK was regularly administered by gavage for 2 weeks. The results of the water maze test revealed that the escape latency in the vehicle group was significantly longer than that in the sham group, and rats in the vehicle group spent a smaller proportion of time in the target quadrant than those in the sham group. SK treatment reduced the escape latencies and increased the proportion of time spent in the target quadrant. Nissl staining showed morphological damage in the CA1 areas of the hippocampus in the vehicle group. SK treatment alleviated the injuries to hippocampal neurons. Western blot analysis showed higher p-PTEN and lower p-Akt, p-CREB, and BDNF expression in the vehicle group than in the sham group. SK administration reversed the upregulation of p-PTEN and the downregulation of p-Akt, p-CREB, and BDNF. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling- (TUNEL-) positive cells in the hippocampal CA1 region of the vehicle group was significantly increased. Treatment with SK decreased the number of positive cells. Furthermore, as marker proteins of apoptosis, bcl-2 expression was decreased and bax expression was increased; thus, the ratio of bcl-2/bax was decreased in the vehicle group. SK treatment upregulated the expression of bcl-2 and downregulated the expression of bax, thereby elevating the bcl-2/bax ratio. Moreover, the aforementioned effects of SK were dose-dependent. The effect of 25 mg/kg per day was more obvious than that of 10 mg/kg per day. In conclusion, SK inhibited hippocampal neuronal apoptosis to protect against CCH-induced injury by regulating the PTEN/Akt/CREB/BDNF signaling pathway, consequently improving cognitive impairment.

Krüppel-Like Factor 6 Silencing Prevents Oxidative Stress and Neurological Dysfunction Following Intracerebral Hemorrhage via Sirtuin 5/Nrf2/HO-1 Axis.

As a severe neurological deficit, intracerebral hemorrhage (ICH) is associated with overwhelming mortality. Subsequent oxidative stress and neurological dysfunction are likely to cause secondary brain injury. Therefore, this study sought to define the role of Krüppel-like factor 6 (KLF6) and underlying mechanism in oxidative stress and neurological dysfunction following ICH. An in vivo model of ICH was established in rats by injection of autologous blood, and an in vitro ICH cell model was developed in hippocampal neurons by oxyhemoglobin (OxyHb) exposure. Next, gain- and loss-of-function assays were performed in vivo and in vitro to clarify the effect of KLF6 on neurological dysfunction and oxidative stress in ICH rats and neuronal apoptosis and mitochondrial reactive oxygen species in OxyHb-induced hippocampal neurons. KLF6, nuclear factor erythroid 2–related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) were highly expressed in hippocampal tissues of ICH rats, whereas sirtuin 5 (SIRT5) presented a poor expression. Mechanistically, KLF6 bound to the SIRT5 promoter and transcriptionally repressed SIRT5 to activate the Nrf2/HO-1 signaling pathway. KLF6 silencing alleviated neurological dysfunction and oxidative stress in ICH rats and diminished oxidative stress and neuronal apoptosis in OxyHb-induced neurons, whereas SIRT5 overexpression negated its effect. To sum up, KLF6 silencing elevated SIRT5 expression to inactivate the Nrf2/HO-1 signaling pathway, thus attenuating oxidative stress and neurological dysfunction after ICH.

Dexmedetomidine reduces the apoptosis of rat hippocampal neurons via mediating ERK1/2 signal pathway by targeting miR-155

Rat hippocampal neurons were isolated and divided into Normal, oxygen glucose deprivation/reoxygenation (OGD/R), OGD/R + DEX, OGD/R + NC mimic, OGD/R + miR-155 mimic and OGD/R + DEX + miR-155 mimic groups. In OGD/R group, LDH, ROS and MDA levels and apoptosis rate was increased, with up-regulations of miR-155, Cyt c and Bax/Bcl-2 ratio, but decreases of SOD, GSH-Px and MMP levels, as well as down-regulations of p-ERK1/2/ERK1/2. As compared to the OGD/R group, parameters above in the OGD/R + DEX group were ameliorated evidently, while OGD/R + miR-155 mimic group manifested the opposite changes. Besides, miR-155 mimic could abolish the protective effect of DEX on the hippocampal neurons under OGD/R. DEX, via down-regulating the expression of miR-155, could activate the ERK1/2 pathway, thereby mitigating the apoptosis and oxidative stress injury and increasing the MMP, thereby protecting hippocampal cells from OGD/R injury.

MiR-485 inhibits histone deacetylase HDAC5, HIF1α and PFKFB3 expression to alleviate epilepsy in cellular and rodent models.

We investigated the role of microRNA (miR)-485 and its downstream signaling molecules on mediating epilepsy in cellular and rat models. We established a cellular epilepsy model by exposing hippocampal neurons to magnesium and a rat model by treating ICR mice with lithium chloride (127 mg/kg) and pilocarpine (30 mg/kg). We confirmed that miR-485 could bind and inhibit histone deacetylase 5 (HDAC5) and then measured expression of miR-485 and in mice and cells. Cells were transfected with overexpression or knockdown of miR-485, HDAC5, hypoxia-inducible factor-1alpha (HIF1α), or 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme (PFKFB3) to verify their roles in apoptosis, oxidative stress, and inflammation in epileptic hippocampal neurons. Binding relationship between miR-485, HDAC5, HIF1α, and PFKFB3 was verified. Oxidative stress and inflammation marker levels in epilepsy model mice were assessed. miR-485 was downregulated and HDAC5 was upregulated in cell and animal model of epilepsy. Seizure, neuronal apoptosis, oxidative stress (increased SOD and GSH-Px expression and decreased MDA and 8-OHdG expression) and inflammation (reduced IL-1β, TNF-α, and IL-6 expression) were reduced by miR-485 in epileptic cells. HIF1α and PFKFB3 expression was reduced by HDAC5 knockdown in cells, which was recapitulated in vivo. Thus, miR-485 alleviates neuronal damage and epilepsy by inhibiting HDAC5, HIF1α, and PFKFB3.

Poria cocos polysaccharide attenuates damage of nervus in Alzheimer's disease rat model induced by D-galactose and aluminum trichloride.

Poria cocos polysaccharide (PCP) is a compound from Poria cocos, and which is used as a classical tonic agent. This article aims to investigate the effects of PCP on neuronal damage of hippocampus and cognitive function in a rat model of Alzheimer's disease induced by D-galactose and aluminum trichloride. Oxiracetam (ORC) was used as a positive drug in this experiment. The rats were treated with PCP at doses of 100, 200 and 300 mg/kg/day for 30 days and ORC at dose of 346 mg/kg/day after modeling. The results of behavioral test showed that PCP could prevent cognitive decline in Alzheimer's disease rats as assessed by Y-maze test and Morris water maze test. Results of hippocampus slices showed that neurons were integrated and regularly arranged in the groups, which were administered along with PCP. Moreover, PCP could reduce neuronal apoptosis in hippocampus of Alzheimer's disease rats. Furthermore, the activities of superoxide dismutase in the hippocampus were elevated by PCP administration, while acetyl cholinesterase, reactive oxygen, malondialdehyde and inflammatory factors levels were reduced. In addition, we found PCP could attenuate MAPK/NF-κB signal pathway in the hippocampus. All results illustrated that PCP could exert neuroprotective effects at least partly through alleviating oxidative stress, apoptosis, inflammation and inhibiting the MAPK/NF-κB pathway in Alzheimer's disease rats induced by D-galactose and aluminum trichloride.

MIUH Inhibits the Hippocampal Neuron Growth in Fetal Rat by Affecting the PTEN Pathway.

Mild intrauterine hypoperfusion (MIUH) can induce placental dysfunction and lead to long-term changes during the process of brain development. A better understanding of the mechanism of MIUH will help in the development of new neuroprotective strategies for the placental chamber. To better understand the mechanism of the effect of MIUH on the neural development of offspring, we constructed a model of MIUH in pregnant rats. The proliferation, apoptosis, and autophagy of hippocampal neurons in fetal rats were studied via flow cytometry, immunofluorescence staining, JC-1 staining, western blotting, and real-time polymerase chain reaction at different time points (6, 24, 48, and 72 h). The results showed that MIUH significantly inhibited the proliferation of hippocampal neurons and promoted their apoptosis and autophagy. Simultaneously, MIUH could promote PTEN expression and affect the PTEN signaling pathway. bpV, an inhibitor of PTEN, could restore the inhibition of hippocampal nerve cell growth caused by MIUH. MIUH may inhibit neuronal proliferation and promote neuronal apoptosis and autophagy by regulating the PTEN signaling pathway.

Sevoflurane induces neuronal apoptosis via enhancing DNMT3L expression and promoting methylation of PSD95 promoter in postoperative cognitive dysfunction

Postoperative cognitive dysfunction (POCD) is a central nervous system (CNS) complication and occurs quite frequently after anesthesia, especially in elderly patients. DNA (cytosine-5)-methyltransferase 3-like (DNMT3L) is an enzymatically inactive regulatory factor that can modulate gene expression via methylation. Few studies specifically focused on the role of DNMT3L in sevoflurane-induced POCD. The cognitive dysfunction was determined by Morris water maze assay. Hippocampal neuron apoptosis was measured by TdT-mediated dUTP nick-end labeling (TUNEL) assay. Neuron proliferation and apoptosis were measured by cell counting kit-8 (CCK-8) and flow cytometry assay. The expression levels of DNMT3L and postsynaptic density protein-95 (PSD95) were measured by qRT-PCR and western blot. The sevoflurane-induced POCD aging rat model was established for in vivo study. Suppression of DNA methylation by 5-Aza-2′-deoxycytidine (5-AZA; a widely used methylation inhibitor) reversed sevoflurane-induced cognitive dysfunction and hippocampal neuron apoptosis in rats. Moreover, sevoflurane enhanced DNMT3L expression and induced methylation of PSD95 promoter in vivo. In vitro, sevoflurane induced neuronal apoptosis and DNMT3L expression to promote PSD95 methylation. Finally, rescue experiments indicated that sevoflurane induced neuron apoptosis by increasing DNMT3L expression and promoting methylation of PDS95 in POCD. Sevoflurane induced neuronal apoptosis by increasing DNMT3L expression and promoting methylation of PDS95 in vivo and in vitro, providing a novel therapeutic strategy for POCD.

Microglia-derived IL-1β promoted neuronal apoptosis through ER stress-mediated signaling pathway PERK/eIF2α/ATF4/CHOP upon arsenic exposure

Arsenic is the leading toxicant of hazardous environmental chemicals, which is linked with neurotoxicity including cognitive dysfunction, neurodevelopmental alterations and neurodegenerative disorders. It has been suggested that sustained pro-inflammatory response is one of the triggering factors of arsenic-induced neurotoxicity. Microglia, the immune cells in the central nervous system, response to physiological and pathological stress, and release a large array of pro-inflammatory cytokines if activated excessively. Several studies indicated that arsenic was capable of inducing microglia activation, however, the role of the subsequently released pro-inflammatory cytokines in arsenic-induced neurotoxicity remains to be elucidated. Our findings demonstrated that arsenic-induced cognitive dysfunction, microglia activation, up-regulation and release of IL-1β and ER stress-mediated apoptosis could be attenuated by minocycline, a recognized inhibitor of microglia activation. In addition, the IL-1 receptor antagonist IL-1ra diminished arsenic-induced activation of ER stress-mediated apoptotic pathway PERK/eIF2α/ATF4/CHOP and neuronal apoptosis. Our findings provided evidences that arsenic-induced microglia activation also contributed to neuronal apoptosis through pro-inflammatory cytokine. Microglia-derived IL-1β promoted hippocampal neuronal apoptosis through ER stress-mediated PERK/eIF2α/ATF4/CHOP apoptotic pathway. Neuronal apoptosis induced by prolonged activation of microglia was partially involved in the arsenic-induced cognitive dysfunction.