Akiko Yano

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.

Mn-SOD and Bcl-2 Expression After Repeated Hyperbaric Oxygenation

To clarify the mechanism of ischemic tolerance induced by HBO, we investigated the effect of HBO on immunoreactivity to Bcl-2 and Bax, apoptosis-regulating protein, or Mn-SOD, a radical scavenging system, in the CA1 sector of the gerbil hippocampus. Pretreatment comprising, five sessions at 2 ATA (atmosphere absolute) every other day, but not that comprising, ten sessions at 3 ATA every day, caused significant increases in Bcl-2 and Mn-SOD immunoreactivity in the CA1 sector compared with in the sham pretreatment group. No significant differences in Bax immunoreactivity and neuronal density in the CA1 hippocampal neurons was observed between the groups. These results suggest that protection against mitochondrial alterations after ischemia through Mn-SOD and/or Bcl-2 expression is related to the ischemic tolerance induced by repeated HBO pre-treatment.

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.

Alteration of gap junction proteins (connexins) following lateral fluid percussion injury in rats

Gap junctions are intercellular channels that mediate the cytoplasmic exchange of small hydrophilic molecules and are formed by a family of integral membrane proteins called connexins (Cxs). Cx43 is expressed predominantly in astrocytes, while Cx36 is expressed in neurons. In this study, we show alteration of Cx43 and Cx36 in the hippocampus after traumatic brain injury in rats. Adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury of moderate severity. Brain coronal sections were used for immunohistochemistry with Cx43 and Cx36 antibodies. Cx43 immunoreactivity was increased in reactive astrocytes in the damaged hippocampus 24 hours after injury, and persisted for 72 hours. On the other hand, Cx36 immunoreactivity increased in CA3 neurons 1 hour after injury, and decreased later. These results indicate that gap junctions might participate in the pathophysiological process after traumatic brain injury.

The Role of CD98 in Astrocytic Neoplasms

The high expression of CD98 was reported in some normal tissues, including blood brain barrier, activated lymphocytes, the basal layer of skin, proximal tubles of kidney, placenta, testis and a wide variety of tumors. The CD98 complex consists of an 80–85kD heavy chain (4F2hc/FRP-1) and a 40–45kD light chain. CD98hc, 4F2hc, and FRP-1 are the same glycosylated protein each other and define antigenicity of CD98. LAT1, the sodium-independent L-type amino acid transporter 1, 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 such as glioma cells. Increased LAT1 expression was found in various malignancies including human gliomas. Several studies implicated the important role of LAT1 and 4F2hc in malignant transformation and carcinogenesis. The LAT1-CD98 pathway may represent a unique therapeutic target for cancer intervention.

Subcellular localization of basic fibroblast growth factor and fibroblast growth factor receptor 1 in pituitary adenomas.

The aim of this study was to assess the subcellular localization of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor 1 (FGFR1) in pituitary adenomas. We studied 61 patients who had primary pituitary adenomas and underwent operation. The immunohistochemistry for bFGF, FGFR1, and MIB-1 was examined in paraffin-embedded tissues. The bFGF immunoreactivity in the nucleus was recorded as the bFGF nuclear index, which was calculated as the percentage of tumor cells with the bFGF immunoreactivity in the nuclei when more than 1000 tumor cells were examined. Recurrent adenomas were found in 7 patients during follow-up periods ranging from 8 to 134 months (mean, 57.2). The recurrent adenomas had significantly larger mean bFGF nuclear indices (74.8±28.8%) than the nonrecurrent adenomas (25.4±32.1%,P=0.0003). The bFGF nuclear index also correlated significantly with the maximum tumor diameters and the invasiveness to the cavernous sinuses (Knosp grade) in the adenomas. The cytoplasmic FGFR1 immunoreactivity was inversely correlated (P<0.02) with maximum tumor diameter. Neither cytoplasmic bFGF, cytoplasmic FGFR1, nor MIB-1 staining index showed any relationship with the recurrence of pituitary adenomas. These findings suggest that the nuclear accumulation of bFGF plays an important role in the progression of pituitary adenomas without its receptors.

Vascular endothelial growth factor expression in pituitary adenomas

Vascular endothelial growth factor (VEGF) is known to be a mediator of angiogenesis and vascular permeability. A cystic component and hemorrhage are often found in pituitary adenomas. In the present study we assess the VEGF expression based on immunohistochemical examinations in 48 pituitary adenomas. All the adenomas showed some VEGF immunoreactivity mainly in the cytoplasm of tumor cells. Of the 48 adenoma-cases, 16 cases had a strong VEGF immunoreactivity, 26 cases had a moderate one, and 6 cases had a weak one. On the MR images, a cystic component was found in 16 cases (33.3%), and a hemorrhage was found in 18 cases (37.5%). The VEGF immunoreactivity had a significant relationship with the cystic component but neither the hemorrhage, size, recurrence, or HE classification. These findings suggest that VEGF might play a potential role in the pathogenesis of cystic formation in pituitary adenomas.

Characteristic phosphorylation of the extracellular signal-regulated kinase pathway after kainate-induced seizures in the rat hippocampus

Extracellular signal-regulated kinase (ERK) pathways play a crucial role in cell growth and long-lasting neuronal plasticity. Several studies have shown that phosphorylated-ERK (p-ERK) significantly increases after kainic acid (KA) administration. However, little or no information is available about the spatial distribution of p-ERK after KA-induced seizures. We herein show that KA-induced seizures significantly increase p-ERK in both neurons and astrocytes in rat brain using Western blots and immunohistochemistry. A strong immunoreactivity for p-ERK was induced in the dentate hilar neurons and CA3 neurons 30 mins and 6 hrs after KA injection. In addition, immunoreactivity for p-ERK was seen in astrocytes 6 hrs after KA injection. 72 hrs after KA injection, all pyramidal neurons had died. These findings suggest that the ERK pathway participates in the KA-induced neurotoxicity in the rat hippocampus.

The association of the expression of vascular endothelial growth factor with the cystic component and haemorrhage in pituitary adenoma

Vascular endothelial growth factor (VEGF) is known to be a mediator of angiogenesis and vascular permeability. A cystic component and haemorrhage are often found in pituitary adenomas. We assessed the VEGF expression based on immunohistochemical examinations in 48 pituitary adenomas. All the adenomas showed some VEGF immunoreactivity mainly in the cytoplasm of tumour cells. Of the 48 adenoma-cases, 16 cases had a strong VEGF immunoreactivity, 26 cases had a moderate one, and 6 cases had a weak one. On the MR images, a cystic component was found in 16 cases (33.3%), and a haemorrhage was found in 18 cases (37.5%). The VEGF immunoreactivity had a significant relationship with the cystic component but not the haemorrhage, size, recurrence, or HE classification. These findings suggest that VEGF plays any potential role in the pathogenesis of cystic formation in pituitary adenomas.

Intraischemic hypothermia during pretreatment with sublethal ischemia reduces the induction of ischemic tolerance in the gerbil hippocampus.

We examined whether mild brain hypothermia during pretreatment with sublethal 2-min ischemia affected the tolerance to subsequent lethal 5-min ischemia. The neuronal densities in the hippocampal CA1 sector of gerbils preconditioned at mild brain hypothermia (32% of normal) were significantly lower than those in gerbils preconditioned at brain normothermia (70% of normal). 72-kDa heat-shock protein immunoreactivity in the CA1 sector preconditioned at mild hypothermia was reduced. These results suggest that mild brain hypothermia during pretreatment with sublethal ischemia reduces the tolerance to subsequent lethal ischemia.