Estradiol prevents Aß 25 35-inhibited long-term potentiation induction through enhancing survival of newborn neurons in the dentate gyrus.

AIM AND METHODS: Estradiol (E2) is reported to attenuate ß-amyloid (Aß) accumulation and slow the progression of Alzheimer's disease (AD). This study explored the beneficial effect of E2 in AD using histological examination and electrophysiological recording technique in AD model mice created by intracerebroventricular injection of ß-amyloid 25-35 (Aß 25-35). RESULTS: Infusion of Aß 25-35 reduced the number of newborn neurons in the 2nd week after birth, a critical period for neurite growth, and impaired high-frequency stimulation-dependent long-term potentiation (LTP) induction in perforant path-granular synapses of hippocampal dentate gyrus (DG). Administration of E2 from the 2nd to 4th week after cell birth in Aß 25-35-mice ameliorated the impairment of newborn neurons and LTP induction in DG. Acute application of E2 failed to increase the newborn neurons and rescue LTP induction in the DG of Aß 25-35-mice. CONCLUSIONS: The effect of E2 in Aß 25-35-impaired LTP induction depends on its neuroprotection improvement.

Selenoprotein S expression in the rat brain following focal cerebral ischemia.

Recent studies on cerebral ischemic stroke have demonstrated the importance of the inflammatory response. Ongoing inflammatory insults have been implicated as a secondary mechanism underlying neuronal injury induced by ischemia, and anti-inflammatory strategies have gained considerable interest. Selenoprotein S (SelS), which is an endoplasmic reticulum resident protein, is known to promote cell survival by regulating inflammation. Moreover, SelS has been shown to be responsive to ischemia in cultured astrocytes. A Finnish report revealed that a variation in the SelS gene locus is associated with a higher predisposition to ischemic stroke in humans, suggesting a crucial role for SelS in protection against brain ischemia. However, the time-course of SelS expression following cerebral ischemia in vivo remains unknown. In the present study, we show, for the first time, differential SelS expression from 3 h to 7 days after reperfusion in rats with transient focal cerebral ischemia induced by a 1-h middle cerebral artery occlusion. We found that the SelS protein level decreased in the ischemic core 3-7 days after reperfusion. Furthermore, SelS expression was upregulated in the ischemic penumbra adjacent to the ischemic core 3-7 days after reperfusion and is matched by reactive astrogliosis. Thus, we propose that the upregulation of Sels represents a reaction of astrocytes against inflammatory stimuli, and the findings of this study open a new chapter in the research of the interrelationships between SelS and cerebral ischemic stroke.

Downregulation of gephyrin in temporal lobe epilepsy neurons in humans and a rat model.

Gephyrin, which is a postsynaptic scaffolding protein participated in clustering GABA(A) receptors at inhibitory synapses, has been reported to be involved in temporal lobe epilepsy (TLE) recently. Here, we investigate gephyrin protein expression in the temporal lobe epileptic foci in epileptic patients and experimental animals in order to explore the probable relationship between gephyrin expression and TLE. Using immunohistochemistry, immunofluorescence, and western blot analysis, gephyrin expression was examined in 30 human temporal neocortex samples from patients who underwent surgery to treat drug-refractory TLE and 10 histological normal temporal neocortex from the controls. Meanwhile, we investigated the gephyrin expression in the hippocampus and adjacent neocortex from experimental rats on 24 h, 48 h, 1 week, 2 weeks, 1 month, and 2 months postseizure and from control rats. Gephyrin protein was mainly expressed in the membrane and cytoplasm of neurons in temporal lobe epileptic foci in humans and experimental rats. Gephyrin expression was significantly lower in the temporal neocortex of TLE patients compared to the controls. In experimental rats, the expression of gephyrin in temporal lobe was downregulated in epileptic groups compared to the control group. Gephyrin expression gradually decreased during the acute period and the latent period, but then began to increase below the levels seen in controls during the chronic phase. Our findings suggest that gephyrin may be involved in the development of TLE.

Translocation and neuroprotective properties of transactivator-of-transcription protein-transduction domain-neuroglobin fusion protein in primary cultured cortical neurons.

Ngb (neuroglobin) is a newly discovered hexaco-ordinate globin that is expressed in vertebrate brain and peripheral nervous systems. Expression of Ngb increases in response to oxygen deprivation and protects neurons from hypoxia in vitro and in vivo. However, the lack of its transduction ability into cells resulted in limited neuroprotection. To educe its neuroprotection under hypoxia, a cell-permeable Ngb fusion protein was generated. A rat brain Ngb gene was cloned and fused with a gene fragment encoding the nine-amino-acid TAT PTD (transactivator-of-transcription protein-transduction domain; RKKRRQRRR) of HIV-1 in a prokaryotic expression vector to generate a genetic in-frame N-terminal hexahistidine-tagged) TAT PTD-Ngb fusion protein. It was expressed in soluble form in Escherichia coli BL21(DE3)plysS and purified with Ni(2+)-affinity chromatography. The results showed that the purified fusion protein TAT PTD-Ngb can enter into the primary cultured cortical neurons in a dose-dependent manner when added exogenously to the culture media and can be detected in cells within 48 h. The cell viability under hypoxia was increased and apoptosis induced by hypoxia was decreased after TAT PTD-Ngb was transduced into cortical neurons. The results provide a clue for the research of Ngb and suggest that transduction of TAT PTD-Ngb may be one of the ways for the therapy of CNS (central nervous system) diseases, especially cerebrovascular diseases and neurodegenerative diseases.

Chronic Estradiol Administration During the Early Stage of Alzheimer's Disease Pathology Rescues Adult Hippocampal Neurogenesis and Ameliorates Cognitive Deficits in Aß1-42 Mice.

Alzheimer's disease (AD) is the leading cause of dementia and has become an important public health concern. Accumulating evidence indicates that estradiol can both facilitate and impair memory-related processes and, as a result, the precise nature of the role that estradiol plays during AD pathology remains elusive. Therefore, the present study established a mouse model of AD using stereotactic brain injection of Aß1-42 in which the mice were bilaterally ovariectomized to investigate the effects of 17ß-estradiol (E2) treatment during different stages of the AD process (early and late stages). The cognitive deficits associated with this AD model were significantly ameliorated, and there was a significant increase in hippocampal neurogenesis in Aß1-42 mice that received E2 treatment during the early stage of AD pathology. On the other hand, Aß1-42 mice that received E2 treatment during the late stage of AD pathology did not exhibit any improvements in cognitive function or hippocampal neurogenesis. To reveal the mechanisms, underlying these effects, levels of oxidative stress, activity in death-associated pathways, gliosis, and synaptic function were assessed in the hippocampus. The Aß1-42 mice that received E2 treatment during the early stage of AD pathology exhibited significant reductions in the production of nitric oxide (NO) and reactive oxygen species (ROS), a marked decrease in the activation of Cytochrome-c/Bax/Bcl-2/caspase-3 pathway, a notable decrease in the level of gliosis a significant increase in the number of synapses (ultrastructural investigation), and a marked upregulation in synaptic function-related proteins compared to mice that received E2 treatment during the late stage of AD pathology. Taken together, these findings indicate that E2 treatment during the early stage of AD pathology might be an efficient approach to ameliorate the development of this disease.

Clinical study on minimally invasive liquefaction and drainage of intracerebral hematoma in the treatment of hypertensive putamen hemorrhage.

OBJECTIVE: This study aims to compare the curative effect of different treatment methods of hypertensive putamen hemorrhage, in order to determine an ideal method of treatment; and to explore the curative effect of the application of soft channel technology-minimally invasive liquefaction and drainage of intracerebral hematoma in the treatment of hypertensive putamen hemorrhage. METHODS: Patients with hypertensive cerebral hemorrhage, who were treated in our hospital from January 2015 to January 2016, were included into this study. Patients were divided into three groups: minimally invasive drainage group, internal medical treatment group and craniotomy group. In the minimally invasive drainage group, puncture aspiration and drainage were performed according to different hematoma conditions detected in brain CT, the frontal approach was selected for putamen and intracerebral hemorrhage, and drainage was reserved until the hematoma disappeared in CT detection. Drug therapy was dominated in the internal medical treatment group, while surgery under general anesthesia was performed to remove the hematoma in the craniotomy group. RESULTS: Post-treatment neurological function defect scores in minimally invasive drainage group and internal medical group were 16.14 ± 11.27 and 31.43 ± 10.42, respectively; and the difference was remarkably significant (P< 0.01). Post-treatment neurological function defect scores in the minimally invasive drainage group and craniotomy group were 16.14 ± 11.27 and 24.20 ± 12.23, respectively; and the difference was statistically significant (P< 0.05). There was a remarkable significant difference in ADL1-2 level during followed-up in survival patients between the minimally invasive drainage group and internal medical treatment group (P< 0.01), and there was a significant difference in followed-up mortality between these two groups (P< 0.01). CONCLUSION: Clinical observation and following-up results revealed that minimally invasive drainage treatment was superior to internal medical treatment and craniotomy.

Change of MicroRNA-134, CREB and p-CREB expression in epileptic rat.

OBJECTIVE: To To investigate the changes of MicroRNA-134, CREB and p-CREB expression in epileptic rat brains in order to elucidate the molecular mechanisms of epilepsy, providing new ideas for clinical treatment. METHODS: Sixty-four Spraque-Dawley (SD) rats were divided into groups randomly, including control group, six hours after seizure group, 24-hour group, three-day group, one-week group, two-week group, four-week group, and eight-week group. All groups were placed under a pilocarpine-induced epilepsy model except the control group, and all rats were decapitated in different points of time. Brain specimens were taken for quantitative PCR experiments, immunohistochemistry and Western blot experiments. The results of the epilepsy model groups and the control group were compared. RESULTS: There were no significant differences between the six hours after seizure group, the 24-hour group and the control group about the MicroRNA-134 levels. MicroRNA-134 in the hippocampus tissue of the three-day group significantly reduced compared with the control group; same result was observed with the one-week, two-week, four-week and eight-week groups. The CREB and p-CREB levels in the three-day group's rat hippocampus significantly increased compared with the control group; and the high levels of CREB and p-CREB were constantly maintained in the one-week, two-week, four-week and eight-week groups. CONCLUSIONS: The MicroRNA-134 level of the epileptic rat hippocampus is significantly lower than normal after three days, and continues to maintain a low level; while CREB and p-CREB levels are rsignificantly increased after three days, and continue to remain at a high level. MicroRNA-134 plays a role in inhibiting synaptic plasticity by inhibiting CREB and p-CREB expressions.

SNCA rs3822086 C>T Polymorphism Increases the Susceptibility to Parkinson's Disease in a Chinese Han Population.

OBJECTIVE: Protofibrils of alpha-synuclein mediate neuronal cell death and propagate Parkinson's disease (PD). In this study, we investigated the relationship between the rs3822086 C>T polymorphism located in the fourth intron of the alpha-synuclein (SNCA) gene and susceptibility to PD in a Chinese Han population. METHODS: 146 PD patients and 144 sex- and age-matched healthy individuals (control group) were selected for this study. The SNCA rs3822086 polymorphism was examined in all 300 study subjects by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: The genotype and allele frequencies of the SNCA rs3822086 polymorphism showed significant differences between the PD group and control group (TT: 25.3% vs. 18.8%, p=0.035; CT+TT: 77.4% vs. 66.0%, p=0.031; T allele: 51.4% vs. 42.4%, p=0.030; respectively). Stratified analyses based on gender indicated that male PD patients exhibited higher genotype and allele frequencies of the SNCA rs3822086 polymorphism compared to healthy male controls (TT: 26.7% vs. 13.2%, p=0.011; CC+CT: 73.3% vs. 86.8%, p=0.024; T allele: 51.2% vs. 37.9%, p=0.012; respectively). Age-stratified analyses indicated that the genotype and allele frequencies of the SNCA rs3822086 polymorphism were significantly higher in PD patients older than 60 years in comparison to healthy controls (TT: 32.2% vs. 20.5%, p=0.014; CT+TT: 77.0% vs. 60.2%, p=0.017; T allele: 54.6% vs. 40.3%, p=0.008; respectively). CONCLUSION: Our findings demonstrate that the SNCA rs3822086 C>T polymorphism correlates with increased susceptibility to PD among the Chinese Han population.

Electroencephalogram global field synchronization analysis: a new method for assessing the progress of cognitive decline in Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia. Global field synchronization (GFS) can measure functional synchronization in frequency-domain electroencephalogram (EEG) data. The aim of this study is to explore GFS values and its clinical significance for severity of cognitive decline in AD. EEGs were recorded from 37 AD patients and 37 age-matched healthy individuals. GFS values were calculated in delta, theta, alpha, beta 1, beta 2, beta 3, gamma, and full frequency bands. The Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating scale (CDR) were employed to assess symptom severity in AD patients. Correlation analysis, clustering analysis, and concordance analysis were performed to analyze the relationship between GFS values and MoCA scores in AD patients. GFS values of the beta 1, beta 2, beta 3, and full bands were lower in AD patients than in healthy individuals, and positively correlated with MoCA and CDR scores in the combined group (AD patients and healthy individuals). GFS values were positively correlated with MoCA socres in 3 beta bands and full bands, and with CDR scores in the delta band. There was a good concordance between K-means clustering algorithm calculating of GFS values and MoCA scoring (κ = .913, P < .001). In conclusion, the present results indicated that GFS can serve as an indicator of cognitive decline or impairment in AD patients. Furthermore, the GFS method of EEG holds considerable promise to distinguish mild cognitive impairment from serious cognitive impairment in patients with AD.

Increased expression of annexin A7 in temporal lobe tissue of patients with refractory epilepsy.

Annexin A7 is a member of the family of annexins, which are thought to function in the regulation of calcium homeostasis and the fusion of vesicles. Refractory epilepsy may be related to the imbalance of calcium homeostasis. Our aims are to investigate the expression of Annexin A7 in epileptic brains in comparison with human controls and to explore Annexin A7's possible role in refractory epilepsy. We examined the expression of Annexin A7 via immunohistochemistry, double-label immunofluorescence and western blot. The expression of Annexin A7 was shown to be significantly increased in patients with refractory epilepsy. Double-label immunofluorescence and confocal microscopy disclosed Annexin A7 immunoreactivity in the neurons, which were recognized by the antibody of neuron specific enolase (NSE). The result showed that Annexin A7 may be involved in the pathophysiology of refractory epilepsy and may play a role in developing and maintaining the epilepsy.

Expression and localization of annexin A7 in the rat lithium-pilocarpine model of acquired epilepsy.

BACKGROUND: Annexin A7 (synexin, ANXA7) is a member of annexins, which plays an essential role in the regulation of calcium homeostasis. Considerable evidence shows that the pathogenetic mechanism of acquired epilepsy (AE) has been related to the imbalance of calcium homeostasis. The aim of this study was to investigate ANXA7 expression and cellular localization in the cortex and hippocampus in the rat lithium-pilocarpine model of AE. METHODS: Totally 81 adult healthy male Wistar rats were randomly divided into control group (n = 9) and experimental group (n = 72), the experimental group contained eight subgroups according to sacrifice time (n = 9) (6-hour, 24-hour, 48-hour, 72-hour, 7-day, 15-day, 1-month, and 2-month). In the experimental group, rats were intraperitoneally injected by lithium-pilocarpine to induce AE model. We examined the expression and localization of ANXA7 via immunohistochemistry, double-label immunofluorescence with the use of neuron specific enolase (NSE) antibody, glial fibrillary acidic protein (GFAP) antibody and propidium iodide (PI), respectively. The data of optical density value were analyzed by analysis of variance. RESULTS: ANXA7 expression increased significantly in the experimental groups especially in the acute period (6 hours, 24 hours, and 48 hours after the onset of seizure) using immunohistochemistry. Double-label immunofluorescence and confocal microscopy disclosed that ANXA7 localized in the neurons but not in astrocytes and did not localize in the nucleus, which were performed with anti-NSE, anti-GFAP and PI respectively. CONCLUSION: ANXA7 may play a potential role in the pathogenetic mechanisms of the rat lithium-pilocarpine model of AE.

Signals in pathological CNS extracts of ALS mice promote hMSCs neurogenic differentiation in vitro.

The capability of MSCs to differentiate into neurons has been proven by many studies. Recently, other studies have cast doubt on MSCs neurogenic differentiation with non-physiological chemical inducing agents in vitro. This present study was designed to use conditioned medium to investigate whether signals from pathological condition of ALS were competent to induce a program of neurogenic differentiation in expanded cultures of hMSCs. Incubation of hMSCs with conditioned medium prepared from CNS extracts of ALS mice (SOD1-G93A ALS mice) resulted in a time-dependent morphological change from fibroblast-like into neuron-like, concomitant with increase in the expression of Nestin and subsequent beta-tubulin III, NSE and GAP43. Moreover, signals in pathological CNS extracts of ALS mice were more effective in promoting hMSCs neurogenic differentiation than those in physiological extracts of normal adult mice. These results show that pathological condition of ALS is endowed with capacity to induce hMSCs neurogenic differentiation and hMSCs have shown a potential candidate in cellular therapy for ALS.