Up-regulation of L type amino acid transporter 1 after spinal cord injury in rats.

BACKGROUND: L-type amino acid transporter 1 (LAT1) is proposed to be a major nutrient transporter at the blood brain barrier. LAT1 requires the heavy chain of 4F2 cell surface antigen (4F2hc) for functional expression. METHODS: We investigated the expression of this heterodimeric transporter after traumatic spinal cord injury in rat by using immunohistochemical and western blot analyses. FINDINGS: LAT1 immunoreactivities were up-regulated in the capillary endothelia in close to the injury epicenter 24 hours after injury. It reached a peak at 48 hours after injury, and thereafter decreased. 4F2hc was abundant and unchanged all through the time course after SCI. Western blot analysis under reductive and non-reductive conditions showed that LAT1 and 4F2hc were conjugated as a heterodimeric transporter and the functional regulation was dependent on the light chain, LAT1. CONCLUSIONS: We suggest that LAT1 may be transiently upregulated as part of the tissue-repair process after traumatic contusion injury in the spinal cord.

Role of the activated extracellular signal-regulated kinase pathway on histological and behavioral outcome after traumatic brain injury in rats.

The extracellular signal-regulated kinase (ERK) pathway, which modulates the activity of many transcriptional factors leading to the proliferation of various cells, is activated in lesions in regions of selective vulnerability after traumatic brain injury (TBI). In the present study, using the ERK inhibitor U0126, we investigated the role of the ERK pathway in histopathological and behavioral outcomes after TBI. Adult male Sprague-Dawley rats, weighing 300-400 g were subjected to lateral fluid percussion brain injury. The ERK inhibitor U0126 was injected intravenously before injury at 100, 200 and 400 microg/kg. The severity of CA3 neuronal damage was evaluated by the number of surviving CA3 neurons 7 days after injury. The contusional lesion volume 72 h after injury was analysed using a computer-assisted analysis system. Three different motor skill tasks were measured on days 1-5, 7, 14 and 21 after injury. Pretreatment with U0126 significantly reduced both CA3 neuronal damage and contusional lesion volume after injury. In addition, administration of U0126 ameliorated motor function recovery on days 3, 4 and 5 after injury. Therefore, inhibition of ERK phosphorylation could be a potentially effective therapeutic target after TBI.

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.

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.

Cerebral infarction along the distribution of perforating arteries during aneurysm surgery in a patient with pheochromocytoma--case report.

A 58-year-old woman with refractory hypertension presented with subarachnoid hemorrhage. Digital subtraction angiography and three-dimensional computed tomography (CT) angiography revealed a ruptured left vertebral artery (VA) aneurysm and an unruptured left middle cerebral artery (MCA) aneurysm. The patient successfully underwent neck clipping of the left VA aneurysm. However, CT obtained just after the operation showed an asymptomatic cerebral infarction along the distribution of medial striate arteries of the right anterior cerebral artery in the caudate nucleus. The pathogenesis of the infarction was unknown. Before clipping surgery of the left MCA aneurysm, detailed examinations to find the cause of her refractory hypertension were performed. Laboratory tests revealed plasma serum level of norepinephrine at 15,521 pg/ml (normal range 100-450 pg/ml). Abdominal magnetic resonance imaging revealed a pheochromocytoma in the right adrenal gland. After preoperative management of the pheochromocytoma, the neck of the left MCA aneurysm was successfully clipped. When the patient awakened from anesthesia, she noticed right hemiparesis and motor aphasia. CT showed cerebral infarction along the distribution of lenticulostriate arteries of the left MCA in the putamen. Her symptoms gradually improved, and the pheochromocytoma was removed by laparoscopic surgery. Sustained severe hypertension and depletion of blood volume resulting from excess catecholamine release from the pheochromocytoma may have caused the complications. Hypervolemic fluid infusion and maintenance of normotensive blood pressure during surgery may avoid such ischemic events.

Temporal and spatial profile of phosphorylated connexin43 after traumatic brain injury in rats.

Gap junctions are conductive channels formed by membrane proteins termed connexins (Cx), which permit the intercellular exchange of metabolites, ions, and small molecules. Junctional permeability is regulated by pH, membrane potential, and intracellular secondary messengers. The purpose of this study was to elucidate the expression and distribution of astrocytic gap junctions in the hippocampus and the cortex after traumatic brain injury (TBI) in vivo. Adult male Sprague-Dawley rats (300-400 g) were subjected to lateral fluid percussion injury (FPI) at moderate severity (2.6-2.8 atm, 12 msec) using a Dragonfly device model. Phosphorylated gap junction protein levels were quantified using Western blot analysis. Spatial distribution of immunoreactivity for phosphorylated Cx43 (p-Cx43) was analyzed by immunohistochemistry. Our findings showed that p-Cx43 expression in the ipsilateral hippocampus was significantly induced at 1 h after TBI, and remained at a high level until 24 h after injury. The p-Cx43 protein content reached a maximum level at 6 h after injury. In addition, the immunoreactivity for p-Cx43 was localized in the astrocytes surrounding ipsilateral CA3 pyramidal neurons. On the other hand, the protein level in the ipsilateral cortex was not significantly different at any time point after TBI. Double immunostaining using phosphorylated ERK (p-ERK) showed that p-Cx43 and p-ERK immunoreactivities were enhanced in the same astrocytes at 6 h after injury. These findings suggest that astrocytic gap junctions participate in pathophysiological processes in the hippocampus after TBI.