Naoki Otani

L-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors

L‐type amino acid transporter 1 (LAT1) is a Na+‐independent neutral amino acid transport agency and essential for the transport of large neutral amino acids. LAT1 has been identified as a light chain of the CD98 heterodimer from C6 glioma cells. LAT1 also corresponds to TA1, an oncofetal antigen that is expressed primarily in fetal tissues and cancer cells. We have investigated for the first time, the expression of the transporter in the human primary astrocytic tumor tissue from 60 patients. LAT1 is unique because it requires an additional single membrane spanning protein, the heavy chain of 4F2 cell surface antigen (4F2hc), for its functional expression. 4F2hc expression was also determined by immunohistochemistry. Kaplan‐Meier analyses demonstrated that high LAT1 expression correlated with poor survival for the study group as a whole (p < 0.0001) and for those with glioblastoma multiforme in particular (p = 0.0001). Cox regression analyses demonstrated that LAT1 expression was one of significant predictors of outcome, independent of all other variables. On the basis of these findings, we also investigated the effect of the specific inhibitor to LAT1, 2‐aminobicyclo‐2 (2,2,1)‐heptane‐2‐carboxylic acid (BCH), on the survival of C6 glioma cells in vitro and in vivo using a rat C6 glioma model. BCH inhibited the growth of C6 glioma cells in vitro and in vivo in a dose‐dependent manner. Kaplan‐Meier survival data of rats treated with BCH were significant. These findings suggest that LAT1 could be one of the molecular targets in glioma therapy.

Anti–high mobility group box-1 antibody therapy for traumatic brain injury

High mobility group box‐1 (HMGB1) plays an important role in triggering inflammatory responses in many types of diseases. In this study, we examined the involvement of HMGB1 in traumatic brain injury (TBI) and evaluated the ability of intravenously administered neutralizing anti‐HMGB1 monoclonal antibody (mAb) to attenuate brain injury.

Differential Activation of Mitogen-Activated Protein Kinase Pathways after Traumatic Brain Injury in the Rat Hippocampus

Mitogen-activated protein kinases, which play a crucial role in signal transduction, are activated by phosphorylation in response to a variety of mitogenic signals. In the present study, the authors used Western blot analysis and immunohistochemistry to show that phosphorylated extracellular signal-regulated protein kinase (p-ERK) and c-Jun NH(2)-terminal kinase (p-JNK), but not p38 mitogen-activated protein kinase, significantly increased in both the neurons and astrocytes after traumatic brain injury in the rat hippocampus. Different immunoreactivities of p-ERK and p-JNK were observed in the pyramidal cell layers and dentate hilar cells immediately after traumatic brain injury. Immunoreactivity for p-JNK was uniformly induced but was only transiently induced throughout all pyramidal cell layers. However, strong immunoreactivity for p-ERK was observed in the dentate hilar cells and the damaged CA3 neurons, along with the appearance of pyknotic morphologic changes. In addition, immunoreactivity for p-ERK was seen in astrocytes surrounding dentate and CA3 pyramidal neurons 6 hours after traumatic brain injury. These findings suggest that ERK and JNK but not p38 cascades may be closely involved in signal transduction in the rat hippocampus after traumatic brain injury.

Enhanced hippocampal neurodegeneration after traumatic or kainate excitotoxicity in GFAP-null mice

Astrocytes perform a variety of functions in the adult central nervous system. Recent evidence suggests that the upregulation of glial fibrillary acidic protein (GFAP), an astrocyte-specific intermediate filament component, is a biological marker of neurotoxicity after cerebral injury. We herein compared the response to traumatic brain injury or kainic acid (KA)-induced neurotoxicity in GFAP knockout (GFAP-KO) and wild-type (WT) mice. Seventy-two hours after injury, all GFAP-KO mice showed hippocampal CA3 neurodegeneration, whereas WT mice did not show neurodegeneration. Seventy-two hours after KA administration, GFAP-KO mice were more susceptible to KA-induced seizures and had an increased number of pyknotic damaged CA3 neurons than did WT mice. These results indicate that GFAP plays a crucial role in pyramidal neuronal survival after injury or KA-induced neurotoxicity.

Surgical management of tuberculum sellae meningioma: Role of selective extradural anterior clinoidectomy

A retrospective analysis of 32 patients with tuberculum sellae meningiomas who underwent surgery via a unilateral pterional approach was performed. A selective extradural anterior clinoidectomy (SEAC) technique was added in 20 patients. All patients had visual dysfunction preoperatively. Macroscopically complete removal with Simpson grade II was performed in 28 patients (87.5%). The postoperative visual function improved in 25 (78.1%), did not change in 3 (9.4%), and worsened in 4 patients (12.5%). The SEAC technique was effective, especially for removal of the tumour extending into the sellae/pituitary stalk (9 patients), the optic canal (4 patients) and hypothalamus (4 patients) with preservation of the visual and endocrinological function. These results were superior to those of surgery without SEAC technique. This technique is therefore recommended for complete resection of the tuberculum sellae meningiomas extending to the surrounding anatomical structures as the SEAC procedure reduces the risk of intraoperative optic nerve injury considerably.

Surgical Outcome following Decompressive Craniectomy for Poor-Grade Aneurysmal Subarachnoid Hemorrhage in Patients with Associated Massive Intracerebral or Sylvian Hematomas

Background: Patients with poor-grade aneurysmal subarachnoid hemorrhage (SAH) presenting with large intracerebral (ICH) or sylvian hematomas (SylH) have poor outcomes due to the mass effect of significant brain stem compression following mass effect. On the other hand, decompressive craniectomy (DC) can reduce morbidity and mortality in critically ill patients with massive ischemic infarction and severe head injury. However, the role of DC in SAH patients is not fully understood. We investigated the outcome of DC in poor-grade SAH presenting with large ICH or SylH. Methods: 110 consecutive patients with poor-grade SAH (Hunt & Kosnik (H&K) grades IV and V, and Fisher group 4) were admitted to our hospital between April 1, 1993, and July 30, 2004. We treated 57 of those who presented with large ICH or SylH using DC. We retrospectively reviewed medical charts, radiological findings, operative notes, and video records. Results: Among the 57 patients (mean age 57.8, male 29, female 28), 25 were classified as H&K grade IV and 32 as grade V. Ruptured aneurysms were located on the internal carotid artery in 11 and the middle cerebral artery in 46 patients. 50 of the aneurysms were small, 5 were medium, and 2 were large. Rerupture was preoperatively confirmed in 13 (22.8%). Hypothermia was applied to 17 (29.8%). The Glasgow Outcome Scale on discharge showed good recovery, moderate recovery, severe disability, vegetative state, and death in 8 (14.0%), 13 (22.8%), 16 (28.1%), 8 (14.0%), and 12 (21.1%), respectively. The outcomes of grade IV patients were favorable and poor in 14 (56.0%) and 10 (40.0%), respectively, and 1 (4.0%) died. Conclusion: Several experimental studies have also indicated that DC significantly improves outcome due to reduced intracranial pressure or increased perfusion pressure. Urgent DC for poor-grade SAH with space-occupying hematoma can lead to survival with good recovery in some patients.

Nuclear accumulation of basic fibroblast growth factor in human astrocytic tumors.

The authors recently reported that nuclear accumulation of basic fibroblast growth factor (bFGF) demonstrated a significant correlation with recurrence of pituitary adenomas. The current study sought to determine whether nuclear bFGF accumulation was a predictor of survival in patients with astrocytic tumors.

Temporal and Spatial Profile of Phosphorylated Mitogen-Activated Protein Kinase Pathways after Lateral Fluid Percussion Injury in the Cortex of the Rat Brain

Mitogen-activated protein kinases (MAPK) play a crucial role in signal transduction that regulates gene expression through transcriptional factor activity. The purpose of this study was to investigate the temporal expression and topographic distribution of the activated MAPK pathways including extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK following traumatic brain injury (TBI) in the cortex of the rat brain. Adult male Sprague-Dawley rats (300-400 g) were subjected to lateral fluid percussion injury of moderate severity (3.5-4.0 atm) using the Dragonfly device model (no. HPD-1700). Phosphorylated-MAPK protein levels were quantified using Western blot analysis. Topographic distribution of immunoreactivity for phosphorylated-MAPK was examined using immunohistochemistry. Our findings showed that TBI significantly increased the phosphorylated-ERK (p-ERK) and -JNK (p-JNK) levels, but not the -p38 (p-p38) protein levels in the cortex surrounding the injury site. The immunoreactivity for p-ERK and p-JNK immediately after TBI were localized in neurons. The immunoreactivity for p-JNK was uniformly but only transiently induced and returned to control levels 1 h after TBI. The immunoreactivity for p-ERK was confirmed up until 30 min after TBI in the superficial neuronal layers. Double immunostaining using a glial-specific marker demonstrated that p-ERK was prominent in astrocytes 6 h after TBI. The current results suggest that the ERK and JNK pathways, but not the p38 MAPK pathways are involved in signal transduction in the cortex following TBI.

Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas.

BACKGROUND xCT is a light chain of the cystine/glutamate antiporter system xc. Glutamate that is released by system xc plays an important role in the infiltration of glioblastoma (GBM) cells. Furthermore, increased glutathione synthesis by system xc may protect tumor cells against oxidative stress induced by radiotherapy and chemotherapy. OBJECTIVE To investigate whether the levels of xCT expression correlated with infiltrative imaging phenotypes on magnetic resonance imaging and outcomes in patients with GBMs. METHODS Forty patients with histologically confirmed primary GBMs were included in the study. Patient charts were retrospectively reviewed for age, sex, Karnofsky Performance Status Scale score, Mini-Mental State Examination score, magnetic resonance imaging features, xCT expression, isocitrate dehydrogenase 1 R132H expression, O-methylguanine-DNA methyltransferase promoter methylation status, type of surgery, progression-free survival, and overall survival. RESULTS In invasive margins, xCT expression was weak in 20 patients and strong in 20 patients. A Cox regression model revealed that a Karnofsky Performance Status Scale score less than 60 (hazard ratio [HR]: 4.525; P = .01), partial removal (HR: 2.839; P = .03), and strong xCT expression (HR: 4.134; P < .001) were significantly associated with shorter progression-free survival and that partial removal (HR: 2.865; P = .03), weak isocitrate dehydrogenase 1 R132H expression (HR: 15.729; P = .01), and strong xCT expression (HR: 2.863; P = .04) were significantly associated with shorter overall survival. CONCLUSION These findings suggest that xCT is an independent predictive factor in GBMs.

Effect of Decompressive Craniectomy on Aquaporin-4 Expression after Lateral Fluid Percussion Injury in Rats

Decompressive craniectomy is one therapeutic option for severe traumatic brain injury (TBI), and it has long been used for the treatment of patients with malignant post-traumatic brain edema. A lack of definitive evidence, however, prevents physicians from drawing any conclusions about the effects of decompressive craniectomy for the treatment of TBI. Therefore, the aim of the present study was to investigate the influence of decompressive craniectomy on post-traumatic brain edema formation. The aquaporin-4 (AQP4) water channel is predominantly expressed in astrocytes, and it plays an important role in the regulation of brain water homeostasis. In the present study, we investigated the time course of AQP4 expression and the water content of traumatized cortex following decompressive craniectomy after TBI. Adult male Sprague-Dawley rats (300-400 g) were subjected to lateral fluid percussion injury using the Dragonfly device. The effect of decompressive craniectomy was studied in traumatized rats without craniectomy (closed skull, DC-), and in rats craniectomized immediately after trauma (DC+). AQP4 expression was investigated with a Western blot analysis and immunohistochemistry. Brain edema was measured using the wet weight/dry weight method. At 48 h after TBI, AQP4 expression of the DC- group was significantly increased compared with the DC+ group (p < 0.01). In addition, the cortical water content of the DC- group was significantly increased compared to the DC+ group at the same time point (p < 0.05). The present results suggest that decompressive craniectomy may affect AQP4 expression and reduce brain edema formation after TBI.