Increased TRPM4 Activity in Cerebral Artery Myocytes Contributes to Cerebral Blood Flow Reduction After Subarachnoid Hemorrhage in Rats.

Cerebral blood flow (CBF) reduction underlies unfavorable outcomes after subarachnoid hemorrhage (SAH). Transient receptor potential melastatin-4 (TRPM4) has a pivotal role in cerebral artery myogenic tone maintenance and CBF regulation under physiological conditions. However, the role of TRPM4 in CBF reduction after SAH is unclear. In this study, we aimed at testing whether TRPM4 would contribute to CBF reduction after SAH in vivo and determining underlying mechanisms. Rat SAH model was established by stereotaxic injection of autologous nonheparinized arterial blood at the suprasellar cistern. A TRPM4 blocker, 9-phenanthrol (9-Phe), was infused through an intraventricular catheter connected to a programmed subcutaneous pump to evaluate the contribution of TRPM4 to SAH outcomes. TRPM4 expression and translocation in cerebral artery myocytes were detected by immunoblotting. Macroscopic currents in cerebral artery myocytes were determined by whole-cell patch clamp. Myogenic tone of cerebral arteries was studied by pressurized myography. Cortical and global CBFs were measured via laser Doppler flowmetry and fluorescent microspheres, respectively. After SAH, TRPM4 translocation and macroscopic current density increased significantly. Furthermore, TRPM4 accounted for a greater proportion of myogenic tone after SAH, suggesting an upregulation of TRPM4 activity in response to SAH. Cortical and global CBFs were reduced after SAH, but were restored significantly by 9-Phe, implying that TRPM4 contributed to CBF reduction after SAH. Collectively, these discoveries show that increased TRPM4 activity has a pivotal role in CBF reduction after SAH, and provide a novel target for the management of cerebral perfusion dysfunction following SAH.

MicroRNA-128 Protects Dopamine Neurons from Apoptosis and Upregulates the Expression of Excitatory Amino Acid Transporter 4 in Parkinson's Disease by Binding to AXIN1.

BACKGROUND/AIMS: Parkinson's disease (PD) is a frequently occurring condition that resulted from the loss of midbrain neurons, which synthesize the neurotransmitter dopamine. In this study, we established mouse models of PD to investigate the expression of microRNA-128 (miR-128) and mechanism through which it affects apoptosis of dopamine (DA) neurons and the expression of excitatory amino acid transporter 4 (EAAT4) via binding to axis inhibition protein 1 (AXIN1). METHODS: Gene expression microarray analysis was performed to screen differentially expressed miRNAs that are associated with PD. The targeting relationship between miR-128 and AXIN1 was verified via a bioinformatics prediction and dual-luciferase reporter gene assay. After separation, DA neurons were subjected to a series of inhibitors, activators and shRNAs to validate the mechanisms of miR-128 in controlling of AXIN1 in PD. Positive protein expression of AXIN1 and EAAT4 in DA neurons was determined using immunocytochemistry. miR-128 expression and the mRNA and protein levels of AXIN1 and EAAT4 were evaluated via RT-qPCR and Western blot analysis, respectively. DA neuron apoptosis was evaluated using TUNEL staining. RESULTS: We identified AXIN1 as an upregulated gene in PD based on the microarray data of GSE7621. AXIN1 was targeted and negatively mediated by miR-128. In the DA neurons, upregulated miR-128 expression or sh-AXIN1 increased the positive expression rate of EAAT4 together with mRNA and protein levels, but decreased the mRNA and protein levels of AXIN1, apoptosis rate along with the positive expression rate of AXIN1; however, the opposite trend was found in response to transfection with miR-128 inhibitors. CONCLUSION: Evidence from experimental models revealed that miR-128 might reduce apoptosis of DA neurons while increasing the expression of EAAT4 which might be related to the downregulation of AXIN1. Thus, miR-128 may serve as a potential target for the treatment of PD.

Correlation between serum S100ß protein levels and cognitive dysfunction in patients with cerebral small vessel disease: a case-control study.

The present study was designed to explore the correlation between serum S100ß levels and cognitive dysfunction in patients with cerebral small vessel disease (SVD). A total of 172 SVD patients participated in the study, and they were assigned to patients with no cognitive impairment (NCI group) and those with vascular cognitive impairment no dementia (VCIND group). In total, 105 people were recruited into the normal control group. Serum S100ß protein level was detected by ELISA. A receiver operating characteristic (ROC) curve was employed for the predictive value of serum S100ß in diagnosing SVD with cognitive dysfunction. Pearson correlation analysis was used to examine the association of S100ß level with mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) and the association of S100ß levels with hypertension. Logistic regression analysis was used to analyze risk factors of SVD. The serum S100ß levels in the VCIND group were higher than those in the NCI and normal control groups. Logistic regression analysis revealed that a high serum S100ß protein level, hypertension, and high low density lipoprotein-cholesterol (LDL-C) level were the independent risk factors for SVD. In addition, hypertension patients showed higher S100ß levels than those with normal blood pressure and the normal control group, and there was a positive correlation between S100ß level and blood pressure. The concentration of serum S100ß level was related to impairment of cognition function of VCIND patients, therefore, early detection of serum S100ß was of great value for diagnosis of SVD.

Management of Pyogenic Cerebral Ventriculitis by Neuroendoscopic Surgery.

BACKGROUND: Pyogenic cerebral ventriculitis is a debilitating form of intracranial infection with an unfavorable outcome as a result of lack of experience in surgical management. OBJECTIVE: To study retrospectively a group of pyogenic cerebral ventriculitis patients managed by neuroendoscopic surgery (NES). METHODS: The standard intraventricular protocols of NES to treat this disease included 1 or more of the following: 1) obliteration of debris, 2) evidence of microbial infection, 3) septomy, 4) incision of the septation, or 5) monitoring catheter insertion. Modified external ventricular drainage EVD (mEVD) was combined with NES when intraventricular debris and bacterial plaques could not be evacuated completely. Subsequent surgical treatment strategies depended on the clinical manifestation, cerebrospinal fluid analysis, and mEVD blockage tests approximately 3 weeks after the last NES. RESULTS: Forty-one patients, who were distributed in 7 hospitals and underwent NES, were included. Five patients received 1 NES, 18 received 2, 16 received 3, and 2 received 4. mEVD was performed in all patients, and mean mEVD duration in the hospital was 27.6 days. At discharge, 15 patients were cured, 15 were cured but ventriculoperitoneal shunt dependent, 9 were mEVD dependent, and 2 died (mean modified Rankin Scale score was 2.48). Two mEVD-dependent patients died, and no other outcomes changed during postoperative follow-up (mean modified Rankin Scale score, 2.67). CONCLUSIONS: The results suggest a relatively favorable outcome for management of pyogenic cerebral ventriculitis by NES. The techniques and strategies are practical and should be applied more extensively.

Rhesus monkey neural stem cell transplantation promotes neural regeneration in rats with hippocampal lesions.

Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells. Therefore, neural stem cell transplantation can be used to promote functional recovery of the nervous system. Rhesus monkey neural stem cells (1 × 105 cells/µL) were injected into bilateral hippocampi of rats with hippocampal lesions. Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well. Transplanted cells were detected at the lesion site, but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum. Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall, and integrated into the recipient brain. Behavioral tests revealed that spatial learning and memory ability improved, indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.

Stent-assisted coiling and balloon-assisted coiling in the management of intracranial aneurysms: A systematic review & meta-analysis.

BACKGROUND: Stent-assisted coiling and balloon-assisted coiling are well-established minimally invasive techniques for treatment of intracranial aneurysms. The aim of this study was to use meta-analysis methods to compare clinical outcomes of aneurysms treated with stent-assisted coiling versus balloon-assisted coiling. METHODS: We searched for two-arm prospective studies and retrospective studies that compared the clinical outcomes in patients that received stent-assisted or balloon-assisted aneurysm treatment. Database search was performed through May 2015. Odds ratios (OR) with 95% confidence intervals (CI) were used to compare the clinical outcomes in patients that underwent either stent-assisted or balloon-assisted coiling for intracranial aneurysms management. RESULTS: Complete occlusion rates at the end of the coiling procedure were similar between patients that received stent-assisted and balloon-assisted aneurysm treatment (OR=0.763, 95% CI=0.47 to 1.23, P=0.270). However, complete occlusion rates were higher with stent-assisted coiling at 6months or later after the procedure (OR=1.82, 95% CI=1.21 to 2.74). The overall complication rates and retreatment rates in patients with recurrence were similar between stent-assisted and balloon-assisted aneurysm treatments. CONCLUSION: Stent-assisted coiling achieved better complete occlusion rates of aneurysms at 6months or later after the procedure compared to balloon-assisted coiling, without being associated with a higher risk of intraprocedural complications and retreatment.

Hyperbaric oxygen therapy for the treatment of traumatic brain injury: a meta-analysis.

Compelling evidence suggests the advantage of hyperbaric oxygen therapy (HBOT) in traumatic brain injury. The present meta-analysis evaluated the outcomes of HBOT in patients with traumatic brain injury (TBI). Prospective studies comparing hyperbaric oxygen therapy vs. control in patients with mild (GCS 13-15) to severe (GCS 3-8) TBI were hand-searched from medical databases using the terms "hyperbaric oxygen therapy, traumatic brain injury, and post-concussion syndrome". Glasgow coma scale (GCS) was the primary outcome, while Glasgow outcome score (GOS), overall mortality, and changes in post-traumatic stress disorder (PTSD) score, constituted the secondary outcomes. The results of eight studies (average age of patients, 23-41 years) reveal a higher post-treatment GCS score in the HBOT group (pooled difference in means = 3.13, 95 % CI 2.34-3.92, P < 0.001), in addition to greater improvement in GOS and lower mortality, as compared to the control group. However, no significant change in the PTSD score was observed. Patients undergoing hyperbaric therapy achieved significant improvement in the GCS and GOS with a lower overall mortality, suggesting its utility as a standard intensive care regimen in traumatic brain injury.

Effect of subarachnoid hemorrhage on voltage-dependence calcium channel current in cerebral artery smooth muscle cells.

OBJECTIVE: To investigate the effect of subarachnoid hemorrhage (SAH) on voltage-dependent calcium channel (VDCC) current in cerebral artery smooth muscle cells (SMCs), oxyhemoglobins (OxyHb) concentration and vasospasm. METHOD: Thirty-six clean SD rats were used to establish SAH model by injecting autologous arterial blood into suprasellar cistern with the aid of stereotaxic instrument. They were divided into arterial SAH group (14 rats), venous SAH group (13 rats) and sham operation group (9 rats), and OxyHb concentrations were measured in the first two groups. Relative membrane surface area of cerebral artery SMCs, resting potential and VDCC current were measured using a patch clamp at day 3 after modeling; cerebral blood flow (CBF) was measured by using fluorescent microsphere-based lateral flow assay. RESULTS: OxyHb concentration of arterial SAH group (127±4 g/L) was higher than that of venous SAH group (54±6 g/L) and sham operation group (50±5 g/L), with significant difference (P<0.05); The maximum VDCC current (3.22±0.31 pA/pF) of the arterial SAH group was obviously higher than that of venous SAH group (2.19±0.27 pA/pF) and sham operation group (2.18±0.29 pA/pF), also showing a significant difference (P<0.05). For arterial SAH group, VDCC current consisted of L- and R-type calcium current, and for venous SAH group the VDCC current consisted of L-type calcium current; CBF of arterial SAH group (0.83±0.14 ml/g/min) was significantly higher than that of venous SAH group (1.28±0.28 ml/g/min) and sham operation group (1.35±0.19 ml/g/min) (P<0.05). CONCLUSION: The effect of arterial SAH was greater on the expression and function of VDCCs in cerebral artery SMCs than venous SAH. This may be explained by the differences in the concentration and composition of pathogenic agents for vasospasm in the arterial and venous blood, such as OxyHb.

Effect of mesenchymal stem cells transplantation combining with hyperbaric oxygen therapy on rehabilitation of rat spinal cord injury.

OBJECTIVE: To investigate the effect of BMSCs transplantation plus hyperbaric oxygen (HBO) on repair of rat SCI. METHODS: Seventy five male rats were divided randomly into five groups: sham, vehicle, BMSCs transplantation group, combination group, 15 rats in each group. Every week after the SCI onset, all animals were evaluated for behavior outcome by Basso-Beattle-Bresnahan (BBB) score and inclined plane test. Axon recovery was examined with focal spinal cord tissue by electron microscope at 6 weeks after the SCI onset. HE staining and BrdU staining were performed to examine the BMSCs and lesion post injury. Somatosensory evoked potential (SEP) testing was performed to detect the recovery of neural conduction. RESULTS: Results from the behavior tests from combination group were significant higher than rats which received only transplantation or HBO treatment. Results from histopathology showed favorable recovery from combination group than other treatment groups. The number of BrdU(+) in combination group were measureable more than transplantation group (P < 0.05). The greatest decrease in TNF-α, IL-1ß, IL-6, IFN-α determined by Elisa assay in combination group were evident too. CONCLUSIONS: BMSCs transplantation can promote the functional recovery of rat hind limbs after SCI, and its combination with HBO has a synergistic effect.

Electroacupuncture in the repair of spinal cord injury: inhibiting the Notch signaling pathway and promoting neural stem cell proliferation.

Electroacupuncture for the treatment of spinal cord injury has a good clinical curative effect, but the underlying mechanism is unclear. In our experiments, the spinal cord of adult Sprague-Dawley rats was clamped for 60 seconds. Dazhui (GV14) and Mingmen (GV4) acupoints of rats were subjected to electroacupuncture. Enzyme-linked immunosorbent assay revealed that the expression of serum inflammatory factors was apparently downregulated in rat models of spinal cord injury after electroacupuncture. Hematoxylin-eosin staining and immunohistochemistry results demonstrated that electroacupuncture contributed to the proliferation of neural stem cells in rat injured spinal cord, and suppressed their differentiation into astrocytes. Real-time quantitative PCR and western blot assays showed that electroacupuncture inhibited activation of the Notch signaling pathway induced by spinal cord injury. These findings indicate that electroacupuncture repaired the injured spinal cord by suppressing the Notch signaling pathway and promoting the proliferation of endogenous neural stem cells.

The effects of hyperbaric oxygen on macrophage polarization after rat spinal cord injury.

The immunoreactive responses are a two-edged sword after spinal cord injury (SCI). Macrophages are the predominant inflammatory cells responsible for this response. However, the mechanism underlying the effects of HBOT on the immunomodulation following SCI is unclear now. The present study was performed to examine the effects of hyperbaric oxygen therapy (HBOT) on macrophage polarization after the rat compressive injury of the spinal cord. HBOT was associated with significant increases in IL-4 and IL-13 levels, and reductions in TNF-α and IFN-É£ levels. This was associated simultaneously with the levels of alternatively activated macrophages (M2 phenotype: arginase-1- or CD206-positive), and decreased levels of classically activated macrophages (M1 phenotype: iNOS- or CD16/32-positive). These changes were associated with functional recovery in the HBOT-transplanted group, which correlated with preserved axons and increased myelin sparing. Our results suggested that HBOT after SCI modified the inflammatory environment by shifting the macrophage phenotype from M1 to M2, which may further promote the axonal extension and functional recovery.

Sexual dysfunction in women after low anterior resection.

Low anterior resection procedures are likely to negatively affect pelvic floor function, which are correlated with sexual dysfunction. The purpose of the study was to explore the prevalence of sexual problems in women with rectal cancer after low anterior resection (LAR). The study consisted of an LAR group (n = 32) and a group of healthy women (n = 32). Female sexual function was evaluated using the Female Sexual Function Index (FSFI). A total of 71.8% of those with LAR reported sexual dysfunction, compared to 18.8% in those who are healthy. The FSFI domain scores were significantly lower for the LAR group relative to the healthy group. Logistic regression revealed that group, education, and age were predictors of female sexual functioning. Women who have had an LAR are at higher risk of sexual function problems. The sexual function of women with LAR should be evaluated in patient discharge planning; nurses should provide more information regarding the impact of LAR on sexual function.

[A DTI study of the contralateral corticospinal tract modeled through simulated intracranial space-occupying lesions in macaque brain motor areas].

Recent studies found that a loss of motor function following corticospinal tract (CST) damage can, to some extent, be restored. Few studies, however, examine how space-occupying lesions in the brain motor area may affect the contralateral CTS structure and function. We performed a simulation of intracranial space-occupying lesions in the brain motor area by implanting of balloons into the brains of the two healthy macaques. Diffusion tensor imaging (DTI) was performed on the macaques' brains four times to measure the FA values of the contralateral CST operative area. The results showed that on the day of balloon implantation, the FA values had no obvious effect, but with time the effect increased, becoming increasingly apparent one week after removing the balloons. Experimental results demonstrated that this model was both feasible and reliable. After the simulated space-occupying lesions occurred in the brain motor area, DTI showed a compensatory response of the contralateral CTS, which remained for a short period of time even after the lesions were removed. This result suggests that the contralateral CST may then also contribute to recovery of limb function.

Blockage of glucocorticoid receptors during memory acquisition, retrieval and reconsolidation prevents the expression of morphine-induced conditioned place preferences in mice.

Association between the reward caused by consuming drugs and the context in which they are consumed is essential in the formation of morphine-induced conditioned place preference (CPP). Glucocorticoid receptor (GRs) activation in different regions of the brain affects reward-based reinforcement and memory processing. A wide array of studies have demonstrated that blockage of GRs in some brain areas can have an effect on reward-related memory; however, to date there have been no systematic studies about the involvement of glucocorticoids (GCs) in morphine-related reward memory. Here, we used the GR antagonist RU38486 to investigate how GRs blockage affects the sensitization and CPP behavior during different phases of reward memory included acquisition, retrieval and reconsolidation. Interestingly, our results showed RU38486 has the ability to impair the acquisition, retrieval and reconsolidation of reward-based memory in CPP and sensitization behavior. But RU38486 by itself cannot induce CPP or conditioned place aversion (CPA) behavior. Our data provide a much more complete picture of the potential effects that glucocorticoids have on the reward memory of different phases and inhibit the sensitization behavior.

[Application of diffusion tensor imaging and 1H-magnetic resonance spectroscopy in diagnosis of traumatic brain injury].

Mild traumatic brain injury (mTBI) is a common type of brain disorders among young adults. The dysfunction of the brain is often exacerbated due to diffuse axonal injury (DAI) which based on the injury of white matter fibers and axons. Since mild and moderate brain injury or DAI are diffuse and subtle, conventional CT and MRI are difficult to make a positive diagnosis. Recent clinical study indicated that functional magnetic resonance imaging has a high detection rate in the diagnosis of acute mild and moderate brain injury, especially the diffusion tensor imaging (DTI) and 1H-magnetic resonance spectroscopy (1H-MRS). This paper has reviewed the principles and characteristics of DTI and 1H-MRS, and recent research in the clinical and animal experiments on brain injury.

[Influences of two different training paradigms on spatial learning and memory performance of hippocampal injured rats].

In this study, the 5 d and 7 d training paradigms were adopted to investigate the influences of different training procedures on the performance of spatial learning and memory of the hippocampal injured rats. The results showed that during the hidden-platform acquisition training, similar spatial learning dysfunctions were indicated in those two training paradigms. Whereas, when the spatial memories have been evaluated, compared with the 5 d training groups, the rats under 7 d training procedure not only crossed the platform location less, but also preferred to spend less time in the target quadrant.

[A technique of rhesus monkey neural progenitor cells intravitreal transplant to rats].

To investigate a simple and effective intraocular xenotransplant technique of rhesus monkey neural progenitor cells to rats, mechanical injury was induced in the rat's right retina. And the GFP-labeled rhesus monkey neural progenitor cells suspension was slowly injected into the vitreous space of the right injured and left control eye. Confocal image suggested that the xenografted cells survived in both the injured and control eye, meanwhile the cells integrated in the injured right retina. The results demonstrated that intravitreal xenotransplant could be adopted as a simple and reliable method.

Survival and number of olfactory ensheathing cells transplanted in contused spinal cord of rats.

OBJECTIVE: To observe the survival and the number of olfactory ensheathing cells (OECs) transplanted in the contused spinal cord, so as to provide a basis for further studying the biological action of OECs. METHODS: The rat spinal cords were contused with NYU-impactor II at T10 level by dropping a 10 g rod from a height of 25 mm. At the 1st week after injury, OECs isolated freshly from green fluorecense protein (GFP) of the rats were transplanted into the spinal cord at injured site and other two sites 1 mm apart from the caudal and rostral ends with the OECs number of 30000/µl x 3 = 90000. The survival and the number of OECs were qualitatively and semi-quantitatively observed under the fluorescense microscope from 1 week to 13 weeks after transplantation. The motor function of the cord was evaluated with BBB score. RESULTS: GFP-OECs could survive at least for 13 weeks within the contused spinal cord. Their arrangement was from tight to loose and their number was decreased from 1 week to 13 weeks after injury. The average number of GFP-OECs was 536 at the 1st week, which was less than 1% of the number as compared with original transplantation. After then, the number of GFP-OECs was continually decreased, but the most obvious decrease was found during 1 week to 2 weeks. The extent of decrease at other time points was relatively mild. In contrast to the cell number, motor function of the cord was gradually recovered after transplantation. CONCLUSIONS: The survival and the number of GFP-OECs are different between the animals and are affected by the pathological reaction of the host cord. Also it is related to the motor function recovery of the contused cord.

[Expression of VEGF and NGF in gliomas of human].

OBJECTIVE: To examine the expression of vascular endothelial cell growth factor (VEGF) and nerve growth factor (NGF) in gliomas of human, and investigate the relationship between VEGF, NGF and pathologic grading as well as tumorigenesis of gliomas. METHODS: Immunohistochemistry (SP) and Western blot were applied to evaluate the expression of VEGF and NGF in 5 cases of normal controls and 20 cases of human gliomas. RESULTS: VEGF and NGF were expressed in both normal brain tissues and gliomas. VEGF was observed mainly in the cytoplasm of gliomas, while NGF were occurred in both cytoplasm and nucleus of gliomas. Western blot analysis demonstrated that the expression level of VEGF and NGF was significantly higher than that in normal controls (P< 0.05), and a significant difference in vary pathologic grading gliomas was also observed. CONCLUSION: VEGF and NGF were expressed in both the normal brain tissues and gliomas. The level of VEGF and NGF in gliomas was upregulated than that of the normal controls. The results indicate VEGF and NGF may play an important role in the tumorigenesis of gliomas, and relate to the extent of gliomas malignant.

[Study on the expression of BDNF in human gliomas].

OBJECTIVE: To investigate the expression of brain-derived neurotrophic factors (BDNF) in gliomas of human, and explore the relation between BDNF and pathologic grading and tumorigenesis of gliomas. METHODS: Immunohistochemistry (SP) and Western blot were applied to evaluate the expression of BDNF in 5 cases of normal controls and 20 cases of gliomas from different pathologic grading. RESULTS: The expression of BDNF was observed mainly occurred in the cytoplasm of both normal brain tissues and gliomas. Western blot analysis showed that the expression level of BDNF in gliomas was significantly higher than that of normal controls (P<0.05), and a gradually increased expression of BDNF in vary pathologic grading (grade I, II, III, IV) gliomas was also observed. CONCLUSION: The expression of BDNF in gliomas of human was greatly upregulated, indicating BDNF may play an important role in the tumorigenesis of gliomas, and relate with pathologic grading.