Cerebral corridor creator for resection of trigone ventricular tumors: Two case reports.

BACKGROUND: Resection of deep intracranial tumors requires significant brain retraction, which frequently causes brain damage. In particular, tumor in the trigone of the lateral ventricular presents a surgical challenge due to its inaccessible location and intricate adjacent relationships with essential structures such as the optic radiation (OR) fibers. New brain retraction systems have been developed to minimize retraction-associated injury. To date, there is little evidence supporting the superiority of any retraction system in preserving the white matter tract integrity. This report illustrates the initial surgical excision in two patients using a new retraction system termed the cerebral corridor creator (CCC) and demonstrates its advantage in protecting OR fibers. CASE SUMMARY: We report two patients with nonspecific symptoms, who had trigone ventricular lesions that involved the neighboring OR identified on preoperative diffusion tensor imaging (DTI). Both patients underwent successful surgical excision using the CCC. Total tumor removal was achieved without additional neurological deficit. DTI showed that the OR fibers were preserved along the surgical field. Preoperative symptoms were alleviated immediately after surgery. Clinical outcomes were improved according to the Glasgow-Outcome-Scale and Activity-of-Daily-Living Scale assessments. CONCLUSION: In the two cases, the CCC was a safe and useful tool for creating access to the deep trigonal area while preserving the white matter tract integrity. The CCC is thus a promising alternative brain retractor.

Bone marrow mesenchymal stem cells upregulate PI3K/AKT pathway and down-regulate NF-κB pathway by secreting glial cell-derived neurotrophic factors to regulate microglial polarization and alleviate deafferentation pain in rats.

Deafferentation pain (DP), a typical neuropathic pain, occurs due to peripheral or central sensory nerve injury, which causes abnormal discharge of the upstream neurons or C fibers. Current treatment methods for DP have multiple side effects. Bone marrow mesenchymal stem cells (BMSC) have been used to treat neuropathic pain because of their ability to regulate neuroinflammation. Glial cell-derived neurotrophic factor (GDNF) is a neurotrophic mediator that exerts neuroprotective effects in neurological diseases. In this study, we investigated whether DP could be alleviated by BMSCs and the underlying mechanism. In vitro study, microglia was stimulated by lipopolysaccharide and then co-cultured with BMSC, GDNF or siRNA GDNF-BMSC. In vivo study, BMSC or siRNA GDNF-BMSC was transplanted intramedullarily on the 21st day after DP surgery. The expression of inflammatory-related factors were detected by RT-PCR and ELISA, RT-PCR,flow cytometry and immunofluorescence staining were performed to detect the expression of microglial surface markers, and Western blot was used to detect the expression levels of p-NF-kb, pPI3K, and pAKT. The pain-related behavioral changes were detected 7 days after transplantation. ELISA and RT-PCR results showed that the production of inflammatory cytokines in lipopolysaccharide-stimulated microglia and DP model plasma was downregulated, while anti-inflammatory mediators were upregulated significantly following pretreatment with BMSCs or GDNF. Flow cytometry, immunofluorescence staining, and RT-PCR results showed that BMSCs inhibited the microglial M1 phenotype and promoted the M2 phenotype by secreting GDNF. Furthermore, modulation functions of BMSCs involve inhibiting NF-κB while promoting PI3K /AKT signaling pathway activation. We found that our in vivo DP model was completely deafferent and BMSC administration clearly alleviated symptoms of DP. This function was also, at least partly, achieved by GDNF. The present studies demonstrate that BMSC can inhibit neuroinflammation by transforming microglial destructive M1 phenotype into regenerative M2 phenotype, and thus alleviate DP,likely by suppressing the NF-κB signaling pathway while promoting the PI3K/AKT signaling pathway activation through producing GDNF. The present findings are in support of the potential therapeutic application of BMSCs and the pharmaceutical application of GDNF for DP.

Adipose-Derived Stem Cells Modulate BV2 Microglial M1/M2 Polarization by Producing GDNF.

Neuroinflammation is associated with the pathogenesis of all types of neurological disease, in which microglial cells play a critical role. In response to disturbances in the microenvironment, microglia (MG) become activated and differentiate into either an M1 phenotype, which has a proinflammatory damaging effect, or an M2 phenotype, which plays an anti-inflammatory and reparative role. Thus, modulating microglial polarization is a suitable strategy to treat neuroinflammatory disorders. Glial cell-derived neurotrophic factor (GDNF) is a neurotrophic mediator that exerts neuroprotective effects during neurological diseases. In this study, we predicted that adipose-derived stem cells (ADSCs) could produce GDNF and investigated the effects of GDNF on microglial M1/M2 polarization. Furthermore, we determined whether GDNF modulates microglial activation and polarization via the phosphoinositide-3-kinase (PI3K)/AKT signaling pathway. We found that the secretion of inflammatory cytokines in lipopolysaccharide-stimulated MG was downregulated, whereas the anti-inflammatory mediators in interleukin-4-stimulated MG were upregulated obviously, following pretreatment with ADSCs or GDNF. In addition, GDNF produced by ADSCs inhibited the MG M1 phenotype and promoted the M2 phenotype by upregulating the PI3K/ATK pathway. These results reveal that GDNF produced by ADSCs might be useful for the regulation of neuroinflammatory disorders.

Dynamic MRI of rat brain following manganese administration through the internal carotid artery.

OBJECTIVE: In this study, we investigated the dynamic distribution processes of Mn(2+) in rat brain using magnetic resonance imaging (MRI) after an intra-arterial (IA) injection of MnCl2 and following the breaking of the blood-brain barrier (BBB). METHODS: Adult male Sprague-Dawley (SD) rats were employed in the study. After the rats were anesthetized with urethane, 25% mannitol was administrated into the right internal carotid artery (ICA) in order to disrupt the BBB, 50 mmol/l (10 mg/kg) of MnCl2 was then injected into ICA prior to the MRI assay. The MRI was performed at 7 T for a continuous 2 hours following the administration of MnCl2. Image reconstruction and analysis were performed using the Statistical Parametric Mapping (SPM) software. RESULTS: As time progressed, the Mn(2+) enhanced signal intensity showed a gradual increase with a maximum increase at 10 minutes following MnCl2 administration, and began to decline after 10 minutes. From 30 minutes to 2 hours, the signal-enhanced region became more homogeneous, and the signal-enhanced range spread to the contralateral area up to 2 hours after MnCl2 administration. CONCLUSION: These results will help future research to select an appropriate time point to perform functional MRI for different types of activity-induced manganese (AIM) MRI research studies. These findings will allow researchers to discriminate intended, stimulation-specific enhanced signal from unintended, nonspecific enhanced signals.

Determination of the detectable concentration of manganese used in neuronal MEMRI and its effect on cortical neurons in vitro.

OBJECTIVE: Manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI) has received increasing attention because of its functional and anatomic value in brain studies. However, the contrast agent, Mn(2+), will lead to neurotoxicity at high concentrations, which limits its use in biomedical research. This study was designed to determine whether Mn(2+) can significantly enhance the signal intensity (SI) of primary cultured cortical neurons at non-toxic levels. METHOD: Neurons were incubated with different concentrations of Mn(2+) (control and 0.01, 0.05, 0.10, and 0.20 mM), then a cellular MRI was performed in vitro and the intracellular Mn(2+) concentrations were analyzed by ICP-MS. At the same time, the cell viability, LDH release assay, intracellular ROS level, and apoptosis were measured 24 h after treatment. RESULTS: (1) After the neurons were treated with Mn(2+) at a low concentration (0.01 mM), there was no impact on cell viability and cytotoxicity, and no significant signal was enhanced on MEMRI. (2) When the neurons were exposed to higher concentrations of Mn(2+) (0.05, 0.1, and 0.2 mM), a significant increase in signal quality was achieved, but cell viability was significantly reduced and the intracellular ROS formation and percentage of TUNEL-positive cells were increased significantly. CONCLUSION: At Mn(2+) concentrations > 0.05 mM, significant enhancement of MEMRI SI occurred, but with overt cytotoxicity.

Adult rat hippocampus soluble factors: a novel transplantation model mimicking intracranial microenvironment for tracing the induction and differentiation of adipose-derived stromal cells in vitro.

Intracranial transplantation of ADSCs induces recovery of CNS diseases, but how they develop in host is poorly understood. The aim of this study is to observe induction and differentiation of ADSCs in the presence of hippocampus soluble factors (HiSF) extracted from the hippocampus of adult Wistar rats to mimic an intracranial microenvironment. To determine the optimal microenvironment, five conditions were tested: 0µg/ml (as control), 50µg/ml, 100µg/ml, 200µg/ml, and 400µg/ml of HiSF. The number of neurospheres was significantly higher in 200µg/ml group than in other groups on the sixth day. Immunofluorescence demonstrated that the neurospheres induced from ADSCs in 200µg/ml group expressed both nestin and CD133, which are more highly expressed in neurospheres than in ADSCs. This result was confirmed by Western blot analysis. Quantitative PCR revealed that the mRNA levels of nestin and CD133 in the neurospheres were 145- and 220-fold higher, respectively, than those in ADSCs. In the presence of 200µg/ml HiSF and 1% FBS, the neurospheres can further differentiate into Schwann-like cells which expressing characteristic markers GFAP, S100 and P75 NGFR. These data indicated that HiSF, mimicking a destination of ADSCs transplanted model in vitro, could effectively induce and differentiate neurospheres, representing a new method to obtain NSCs and Schwann-like cells from ADSCs.

P53-induced microRNA-107 inhibits proliferation of glioma cells and down-regulates the expression of CDK6 and Notch-2.

MicroRNAs (miRNAs) are small noncoding RNAs that function as tumor suppressors or oncogenes. MicroRNA-107 (miR-107), a transcriptional target of p53, is deregulated in many cancer cell lines. Here, we showed that miR-107 is down-regulated in glioma tissues and cell lines, in particular, p53-mutated U251 and A172. Transfection of wild-type p53 into these cells stimulated miR-107 expression. To investigate the role of miR-107 in tumorigenesis, we constructed a lentiviral vector overexpressing miR-107. Notably, miR-107 inhibited proliferation and arrested the cell cycle at the G0-G1 phase in glioma cells. Transduction of Lenti-GFP-miR-107 into glioma cells inhibited CDK6 and Notch-2 protein expression. Our findings collectively demonstrate that p53-induced miR-107 suppresses brain tumor cell growth and down-regulates CDK6 and Notch-2 expression, supporting its tumor suppressor role and utility as a target for glioma therapy.

Potential of placenta-derived mesenchymal stem cells as seed cells for bone tissue engineering: preliminary study of osteoblastic differentiation and immunogenicity.

Mesenchymal stem cells (MSCs) have been isolated from a variety of human tissues (eg, bone marrow, peripheral blood, muscle, fat, umbilical blood, amniotic fluid, embryonic tissues, and placenta). Placenta-derived MSCs (PDMSCs) have received considerable interest because of their wide availability and absence of ethical concerns. The authors characterized the biological properties, ultrastructure, growth factor production, and osteoblastic differentiation of PDMSCs and investigated their potential as seed cells for bone tissue engineering.

[Motor function evaluation in rats receiving umbilical cord mesenchymal stromal cell transplantation for traumatic brain injury using CatWalk automated gait analysis system].

OBJECTIVE: To assess the effect of CatWalk automated gait analysis system for evaluation of motor function of rats with traumatic brain injury (TBI) after umbilical cord mesenchymal stromal cell (UC-MSC) treatment. METHODS: Eighteen Wistar rats were randomized equally into normal control group, TBI ∓ saline group, and TBI ∓ UC-MSCs group. The rats in the latter two groups were subjected to weight-drop impact to induce TBI followed by injection UC-MSCs or saline into the lesion 7 days after TBI. The neurological function was assessed using CatWalk system and modified neurological severity scores (mNSS) before and 3 days after TBI and 7 days after UC-MSC transplantation. The rats were sacrificed 14 days after the cell transplantation and the brain sections were stained for immunohistochemical analyses. RESULTS: Three days after TBI, mNSS test showed moderate injury of the rats. Seven days after the cell transplantation, the rats showed significant motor function improvement and CatWalk analysis indicated partial recovery of the gait parameters of the 4 limbs compared to the rats with saline treatment. Histological analyses showed that DiO-labeled UC-MSCs were present in the lesion boundary and expressed glial fibrillary acidic protein and ß-tubulin III. CONCLUSION: UC-MSC transplantation can promote functional improvement of the brain after TBI in rats. Compared with mNSS test, CatWalk analysis is more sensitive and objective for assessing neurological function and also provides more detailed information on specific gait parameters.

Functional mapping of rat brain activation following rTMS using activity-induced manganese-dependent contrast.

OBJECTIVE: Functional neuroimaging techniques act as the navigator to assess changes in brain activity induced by repetitive transcranial magnetic stimulation (rTMS) in rTMS studies. The aim of this study was to investigate the feasibility of using manganese-enhanced magnetic resonance imaging (MEMRI) to measure the brain activity in rTMS studies. METHODS: Eighteen Wistar rats were randomized into three groups (n = 6) including a high rTMS group, a low rTMS group and a sham stimulation group (controls). They were given rTMS of 10 Hz, 1 Hz or sham stimulation for 5 hours separately. MEMRI was used to assess the changes of brain activity. RESULTS: Compared with the controls, image intensity was enhanced differently in various brain regions on T1-weighted images after rTMS with different frequencies, higher intensity and wider enhancement occurred in the high frequency rTMS group as compared with that in the low frequency rTMS group. CONCLUSION: MEMRI can be used to reveal the changes of brain activity in live rats following rTMS. SIGNIFICANCE: The current experiment might provide a new functional neuroimaging technique for the study of rTMS.

Effects of temporarily disrupting BBB on activity-induced manganese-dependent functional MRI.

This study further investigates the influence of temporarily disrupting the blood-brain barrier (BBB) on the level of manganese used in AIM fMRI other than the recognized function of allowing that substance to enter into the activated brain regions more effectively during the BBB opening. We injected manganese into Wistar rats through ICA following the disruption of BBB with mannitol in a functional MRI test of the visual cortex. Through comparing MRI signal intensity and manganese contents in the visual cortex of rats received visual stimuli of unequal degree after the restoration of BBB, we found that the signal in the visual cortex could be further enhanced on T1WI given visual stimulation after the restoration of BBB. Temporary BBB disruption has an additional advantage in allowing Mn(2+) to enter the CSF or brain for later transference to the activated brain area. So the dosage of manganese in AIM fMRI could be minimized by extending the stimulus.

Activity-induced manganese-dependent functional MRI of the rat visual cortex following intranasal manganese chloride administration.

Manganese-enhanced MRI (MEMRI) of the brain requires delivery of manganese into the target brain regions. It was previously shown that, following intranasal application, ongoing olfactory stimulation facilitates manganese transport along the olfactory nerve into the olfactory bulb, so bypassing the blood-brain barrier (BBB). We report on experiments to evaluate whether visual stimulation can permit manganese transport onwards from the olfactory bulb to the visual cortex. Rats in intact olfactory bulb group were reserved intact olfactory bulb, while those in olfactory bulbectomy group received bilateral bulbectomy. After intranasal MnCl(2) administration, olfactory and visual stimulations were performed on all the animals for a consecutive 20 h. The visual cortex was then examined using MEMRI. Enhanced imaging on T1WI was noted in the visual cortex of the intact olfactory bulb group. Image subtraction revealed that the signal intensity in the visual cortex of the intact olfactory bulb group was significantly higher than that of olfactory bulbectomy group. Volume of interest (VOI) analysis also showed that normalized intensities in the visual cortex of the intact olfactory bulb group were significantly higher as compared with those of the olfactory bulbectomy group. Inductively coupled plasma mass spectrometry (ICP-MS) confirmed that the manganese content in the visual cortex of the intact olfactory bulb group was increased in comparison with that of the olfactory bulbectomy group. These findings indicate that activity-induced manganese-dependent functional MRI (AIM fMRI) of the rat visual cortex can be performed following intranasal administration of manganese and demonstrate that manganese can migrate from the olfactory bulb to the visual cortex.

[Association of blood and cerebrospinal fluid IgG contents and severity of craniocerebral injury].

OBJECTIVE: To explore the association of blood and cerebrospinal fluid (CSF) IgG contents and the severity of craniocerebral injury. METHODS: Totalling 143 patients with craniocerebral injury were divided into 3 groups according Glasgow Coma Scale (GCS) scores, namely the mild injury group with GCS score of 12-15 (n=41), moderate injury group with GCS score of 9-11 (n=71) and severe injury group (GCS score 3-8, n=32). Another 9 patients with congenital hydrocephalus were also recruited as the control group. The CSF and blood samples were collected from these patients to measure the IgG contents 4 and 14 days and 1, 2, and 6 months after the injury, respectively. Physical disabilities of the patients were estimated with Rappaport's disability rating scale (DRS), whose correlations with CSF and blood IgG contents were analyzed. RESULTS: In the early stage of moderate to severe brain injury, the IgG content was lowered significantly in the blood but increased in CSF as compared with the control patients (P<0.05), and the changes in CSF and blood IgG displayed a significant correlation with the severity of the injury (r=0.950, P<0.01). During the recovery of severe brain injury, DRS score was in inverse correlation with blood IgG content but in positive correlation with CSF IgG content (Spearman's correlation coefficient of 0.800, P<0.05). CONCLUSION: In the early stage of brain injury, detection of blood IgG content may help with the assessment of the injury severity. During the recovery of the injury, dynamic monitoring of blood and CSF IgG contents provides clues of the outcome of the patients and benefit the modification of the treatment plan.