Selective vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury.

A secondary and often lethal consequence of traumatic brain injury is cellular edema that we posit is due to astrocytic swelling caused by transmembrane water fluxes augmented by vasopressin-regulated aquaporin-4 (AQP4). We therefore tested whether vasopressin 1a receptor (V1aR) inhibition would suppress astrocyte AQP4, reduce astrocytic edema, and thereby diminish TBI-induced edematous changes. V1aR inhibition by SR49059 significantly reduced brain edema after cortical contusion injury (CCI) in rat 5h post-injury. Injured-hemisphere brain water content (n=6 animals/group) and astrocytic area (n=3/group) were significantly higher in CCI-vehicle (80.5±0.3%; 18.0±1.4 µm(2)) versus sham groups (78.3±0.1%; 9.5±0.9 µm(2)), and SR49059 blunted CCI-induced increases in brain edema (79.0±0.2%; 9.4±0.8µm(2)). CCI significantly up-regulated GFAP, V1aR and AQP4 protein levels and SR49059 suppressed injury induced up regulation (n=6/group). In CCI-vehicle, sham and CCI-SR49059 groups, GFAP was 1.58±0.04, 0.47±0.02, and 0.81±0.03, respectively; V1aR was 1.00±0.06, 0.45±0.05, and 0.46±0.09; and AQP4 was 2.03±0.34, 0.49±0.04, and 0.92±0.22. Confocal immunohistochemistry gave analogous results. In CCI-vehicle, sham and CCI-SR49059 groups, fluorescence intensity of GFAP was 349±38, 56±5, and 244±30, respectively, V1aR was 601±71, 117.8±14, and 390±76, and AQP4 was 818±117, 158±5, and 458±55 (n=3/group). The results support that edema was predominantly cellular following CCI and documented that V1aR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, V1A and AQP4, blunting edematous changes. Our findings suggest V1aR inhibitors may be potential therapeutic tools to prevent cellular swelling and provide treatment for post-traumatic brain edema.

Brain energy depletion in a rodent model of diffuse traumatic brain injury is not prevented with administration of sodium lactate.

Lactate has been identified as an alternative fuel for the brain in situations of increased energy demand, as following a traumatic brain injury (TBI). This study investigates the effect of treatment with sodium lactate (NaLac) on the changes in brain energy state induced by a severe diffuse TBI. Rats were assigned to one of the eight groups (n=10 per group): 1-sham, normal saline; 2-TBI, normal saline; 3-TBI, hypertonic saline; 4-TBI, 100mM NaLac, 5-TBI, 500 mM NaLac; 6-TBI, 1280 mM NaLac; 7-TBI, 2000 mM NaLac and 8-TBI-500 mM NaLac+magnesium sulfate. Cerebrums were removed 6h after trauma. Metabolites representative of the energy state (ATP, ATP-catabolites), N-acetylaspartate (NAA), antioxidant defenses (ascorbic acid, glutathione), markers of oxidative stress (malondialdehyde, ADP-ribose) and nicotinic coenzymes (NAD(+)) were measured by HPLC. TBI induced a marked decrease in the cerebral levels of ATP, NAA, ascorbic acid, glutathione and NAD(+) and a significant rise in the content of ATP-catabolites, malondialdehyde and ADP-ribose. These alterations were not ameliorated with NaLac infusion. We observed a significant reduction in cerebral NAD(+), an essential co-enzyme for mitochondrial lactate-dehydrogenase that converts lactate into pyruvate and thus replenishes the tricarboxylic acid cycle. These results suggest that the metabolic pathway necessary to consume lactate may be compromised following a severe diffuse TBI in rats.

Effect of secondary insults upon aquaporin-4 water channels following experimental cortical contusion in rats.

Although secondary insults of hypoxia and hypotension (HH) are generally considered to cause fulminant brain edema in traumatic brain injury (TBI), the combined effect of TBI with HH on brain edema and specifically the expression of aquaporin-4 (AQP4) have not been fully elucidated. The goal of this study was to document the effect of secondary insults on brain water, AQP4 expression, electrolytes, and blood-brain barrier (BBB) permeability during the acute stage of edema development. We measured brain water content and electrolytes (series 1); BBB permeability based on Evans blue (EB) dye extravasation (series 2); and AQP4 expression using immunoblotting (series 3) at 1 h and 5 h following cortical contusion injury (CCI). Secondary insults significantly worsened BBB function at 5 h post injury. Moreover, a significant reduction of upregulation on AQP4 expression was observed in trauma, coupled with a mild secondary insult of hypoxia hypotension. These findings indicate that a secondary insult following CCI at 5 h post injury worsens brain edema, disrupts ionic homeostasis, and blunts the normal upregulation of AQP4 that occurs after trauma, suggesting that the blunting of AQP4 may contribute to the detrimental effects of secondary insults.

Modulation of AQP4 expression by the selective V1a receptor antagonist, SR49059, decreases trauma-induced brain edema.

BACKGROUND: Currently, there are no pharmacological treatments available for traumatically induced brain edema and the subsequent rise of ICP. Evidence indicates that Aquaporin-4 (AQP4) plays a significant role in the pathophysiology of brain edema. Previously we have reported that SR49059 reduced brain edema secondary to ischemia. We, therefore, examined whether the selective V1a receptor antagonist, SR49059, reduces brain edema by modulating AQP4 expression following cortical contusion injury (CCI). METHODS: Traumatic brain injury (TBI) was produced in thirty-two adult male Sprague-Dawley rats by lateral CCI (6.0 m/sec, 3 mm depth). Animals were randomly assigned to vehicle (n=16) or SR49059 treatment (n=16) groups and administered drug (960 microl/hr i.v.) immediately after injury over a 5 hr period. Animals were sacrificed for assessment of brain water content by Wet/Dry method and AQP4 protein expression by immunoblotting expressed as the ratio of AQP4 and Cyclophilin-A densitometries. FINDINGS: Elevated AQP4 expression levels and water content were observed on the right injured side in both the right anterior (RA) and right posterior (RP) section compared to the left non-injured side inclusive of the left anterior (LA) and right anterior (RA) sections. The average AQP4 expression levels in contused areas for animals receiving SR drug treatment (RA: 1.313 +/- 0.172, RP: 1.308 +/- 0.175) were significantly decreased from vehicle-treated animals (RA: 2.181 +/- 0.232, RP: 2.303 +/- 0.370, p = 0.001, p= 0.003). Water content levels on SR treatment (78.89 +/- 0.14) was also significantly decreased from vehicle levels (80.38 +/- 0.38, p < 0.01) in the traumatized hemisphere. CONCLUSIONS: SR49059 significantly reduced trauma-induced AQP4 up-regulation in the contused hemisphere. Moreover, brain water content was also significantly reduced paralleling the AQP4 suppression. These data provide further support that vasopressin (AVP) and V1a receptors can control water flux through astrocytic plasma membranes by regulating AQP4 expression. Taken in concert, these results affirm our laboratories contention that AQP4 can be effectively modulated pharmacologically.

The modulation of aquaporin-4 by using PKC-activator (phorbol myristate acetate) and V1a receptor antagonist (SR49059) following middle cerebral artery occlusion/reperfusion in the rat.

BACKGROUND: We have pursued the concept that traumatic brain edema is predominantly cellular and that water entry is modulated in part by aquaporins. Aquaporin-4 (AQP4) has been shown to play a significant role in cellular edema formation. Phorbol myristate acetate (PMA) is a potent PKC activator; purportedly involved in modulation of AQP4 activity. Alternatively, AQP4 may be regulated by arginine-vasopressin. Administration of the vasopressin antagonist (SR49059) reduced brain water content and sodium shift following MCAo. To investigate if edema formation is affected by the reduction of AQP4 expression, we utilized PMA and SR49059 following middle cerebral artery occlusion model (MCAo), and measured AQP4 expression by Western-Blot (WB) techniques. METHODS: Male Sprague Dawley rats were randomly assigned to sham (n=4) or MCAo groups (vehicle, PMA or SR49059 infusion; n=6 each). Each solution was infused for 5 hours, starting 1 hour before injury. After a two-hour period of ischemia and two-hour reperfusion, animals were sacrificed and brain regions of interest were processed by WB to quantify the effect of treatment on AQP4 expression. RESULTS: These studies demonstrate that MCAo results in a significant up-regulation of AQP4 on the ischemic zone when compared to the contralateral un-injured hemisphere (p < 0.05) and that PMA and SR49059 treatment significantly down-regulated AQP4 expression compared to the vehicle group (p < 0.05). CONCLUSIONS: These studies support the hypotheses that PMA and SR49059 may be useful in reducing cerebral water accumulation by modulating AQP4 expression and that pharmacological manipulation of AQP4 may emerge as a viable strategy for the reduction of fulminating edema following ischemic injury.

[Serum S-100B protein and neuron-specific enolase after traumatic brain injury].

OBJECTIVE: The aim of this study was to investigate S-100B protein and NSE as a serum marker of brain cell damage after traumatic brain injury. MATERIAL AND METHODS: Forty-one patients with traumatic brain injury were included in this prospective study. Venous blood samples for S-100B protein and NSE were taken after admission and on the next day. Serum levels of S-100 protein and NSE were compared with Glasgow Coma Scale score, computed tomographic findings and outcome after 3 months. RESULTS: Serum S-100B protein and NSE were significantly correlated with Glasgow Coma Scale score and outcome after 3 months. The significant correlation was found between the initial S-100B and NSE (P < 0.001). In patients without parenchymal injuries on computed tomographic scan such as epidural hematoma and concussion, the elevation of S-100B protein and NSE was observed. The initial values of S-100B and NSE in acute subdural hematomas with unfavorable outcome were significantly higher than in those with favorable outcome. Secondary increase of serum markers was associated with the presence of secondary insult such as hypoxia or hypotension, and was found to have an unfavorable outcome. CONCLUSIONS: Serum concentration and kinetics of S-100B protein and NSE provide the clinical assessment of the primary brain damage and have a predictive value for outcome after traumatic brain injury.

[Acute spontaneous subdural hematoma of arterial origin].

BACKGROUND: Acute subdural hematoma is usually associated with cerebral contusion or laceration of the bridging veins following a head injury. However, several cases of acute subdural hematoma without head injury (acute spontaneous subdural hematoma) have been reported. METHODS: Among 162 cases of acute subdural hematoma admitted to our departments between 1996 and 2003, we repoort eight cases of acute spontaneous subdural hematoma. These cases fulfilled the following criteria. 1) Head injury was either trivial or absent. 2) Neither aneurysm nor arteriovenous malformation was apparent. 3) CT scan revealed neither brain contusion nor traumatic subarachnoid hemorrhage. 4) At operation, laceration of the cortical artery was observed. In this article, we describe the clinical feature (age, sex, Glasgow Coma Scale [GCS] Score on admission, past history, CT appearance, and outcome) associated with this condition. RESULTS: Patients ranged in age from 68 to 85 years (average 74.8 years), and were comprised of 3 males and 5 females. Previous medical history included cerebral infarction in 6 of the 8 patients and myocardial infarction in 1 patient. These seven patients were taking antiplatelet manifestation. GCS on admission ranged from 4 to 13. Five of the 7 patients on antiplatelet medication had secondary insults, such as hypoxia. On CT, hematoma thickness ranged from 13.2mm to 42.5mm (average 22.6mm), and midline shift ranged from 10.0mm to 24.0mm (average 16.5mm). Neurological outcome evaluated using the Glasgow Outcome Scale was as follows, good recovery n = 2, moderate disability n = 2, severe disability n = 3, persistent vegetative state n = 1. CONCLUSION: The mechanism of acute spontaneous subdural hematoma is influenced by the presence of pre-existing cerebrovascular disease and by the use of antiplatelet agents. In such cases, the possibility of cortical arterial bleeding should be taken into account, and craniotomy should be performed.

[Therapeutic effect of spinal cord stimulation for a patient suffering spasticity after hypoxia of the brain].

We reported a case of severe spasticity of the bilateral upper and lower limbs which was improved by cervical spinal cord stimulation (SCS). A 53-year-old man was suffering from sudden cardiopulmonary arrest while walking. After receiving cardiopulmonary resuscitation for 40 minutes, his cardiopulmonary function re-started, but he failed to regain consciousness. MRI revealed a hypoxic brain in his bilateral basal ganglia and occipital lobes. After 2 months, his consciousness advanced to a vegetative state and the muscle tone of his bilateral upper and lower limbs deteriorated to severe spasticity. SCS was performed in the expectation of improving his consciousness. Contrary to this anticipated result, his vegetative state continued but the severe spasticity of his upper and lower limbs improved during the SCS. Single photon emission computed tomography (SPECT) during the period of stimulation revealed a high blood flow, especially in the area of the basal ganglia, thalamus, brain stem and cerebellum, compared with off-stimulation blood flow. The neurophysiologic mechanisms of these abnormal fields and the underlying aberrant afferent nerve impulses from the posterior funiculus in the cervical cord to the cerebral sensory cortex, which may indeed be secondary to ischemic brain, may be regulated by SCS, also adding the effect of increased blood flow to the brain.

[Spontaneous regression of primary central nervous system lymphoma: a case report].

A rare case of primary central nervous system lymphoma that regressed spontaneously as shown on serial cranial magnetic resonance imagings (MRI) is described. A 60-year-old woman was admitted to our hospital with a well-enhanced mass lesion in the cerebellum although MRI had demonstrated no abnormal findings 4 months before admission. On admission, She complained of headache, but no neurological deficits were observed. The patient underwent exploratory craniotomy and the tumor was partially removed on February 14. Pathologic examination suspected B-cell type of malignant lymphoma. Postoperative MRI performed on February 23, 2001 showed disappearance of the mass lesion without further treatment. Different polymerase chain reaction (PCR) assays detected clonal immunoglobulin heavy chain gene rearrangements in paraffin-embedded tissues diagnosed as B-cell lymphoma. The patient was discharged without any neurological deficits for two weeks and was followed up on MRI. One year after operation, MRI revealed an abnormal finding in the cerebellum without apparent neurological deterioration. Radiation therapy of the whole brain and the local site was carried out with a total dose of 50Gy. MRI demonstrated complete remission of the tumor following radiation therapy. She was admitted again to our hospital with right hemiparesis on May, 2003. Subsequently, systemic chemotherapy was carried out. The patient died 2 years and 10 months after her initial presentation.

[A multicentric glioma presenting different pathological appearances: a case report].

We report a multicentric glioma case which revealed different pathological appearances. A 45-year-old male had been admitted to our hospital complaining of an attack of transient sudden aphasia. On magnetic resonance imaging (MRI), T1-weighted images revealed a low intensity and T2-weighted images demonstrated a homogeneous high intensity abnormal mass in the frontal lobe, which was not enhanced with gadolinium. Removal of the tumor was performed through a right frontal transcortical approach in March, 2002. Histological diagnosis was gemistocytic astrocytoma. The patient's condition was uneventful and postoperative MRI revealed a marked decrease in the volume of the tumor. A total of 54 Gy radiation to the brain in the locality was performed. Four months after the initial surgery, the patient suffered from incomplete right hemiparesis. MRI showed a left parietal abnormal mass which had a ring formation enhancement after gadolinium administration. This Neuro-radiological examination demonstrated complete independence from the initial right frontal tumor. A second surgery which was concerned with cyst aspiration was carried out on August 10, 2002. During the next month, a third operation for partial removal of a left parietal abnormal mass was performed. Histological diagnosis was anaplastic astrocytoma. The right frontal and left parietal tumors revealed neither continuous relation suggesting intracerebral invasion, nor dissemination through the subarachnoid space nor intracerebral metastasis. Our case was diagnosed as multicentric glioma with different pathological appearances, of which only 9 cases have been reported previously.

[Intracranial metastasis of pituitary adenoma: a case report].

Growth hormone-secreting pituitary adenoma is usually benign, and distant metastases are extremely rare. A case of growth hormone-secreting pituitary adenoma with multiple dural metastases is reported. A 53-year-old male was initially admitted to our hospital complaining of visual loss, presenting a pituitary abnormal mass with suprasellar extension. At the initial surgery, transsphenoidal surgery was selected, and the histological finding was benign pituitary adenoma. Seven and 16 months after the initial surgery, second and third surgeries via a transcranium route were performed for recurrence of the pituitary tumor. Histological findings revealed an appearance similar to the initial tumor in both surgical specimens. After the third operation, radiation therapy (local irradiation: total; 44 Gy) was performed. Six years after the first surgery, three tumors were located in the right frontal, parietal convexity and cerebellar tentorium. The tumors were totally removed by 4th and 5th surgeries. Histological examination showed malignant transformation from the primary benign growth hormone-secreting pituitary adenoma, with dural metastasis. Immunohistochemical staining with MIB-1 antibody demonstrated a high index of 7%. The patient is still alive after more than one year since the diagnosis of distant metastasis. According to previous reviews, few patients have survived more than one year. We conclude patients with benign pituitary adenoma should be carefully followed up for fear of malignant transformation or dural metastasis.

[Two cases of lymphocytic infundibuloneurohypophysitis].

We report two cases of lymphocytic infundibuloneurohypophysitis (LIH). A 32-year-old male and a 13-year-old male were admitted to our hospital because of a sudden occurrence of the diabetes insipidus (DI). MRI of both patients showed the disappearance of hyperintensity of the posterior pituitary in T1WI, pituitary stalk swelling and enlargement of the pituitary gland, with homogeneous enhancement by gadolinium. We thereby diagnosed LIH, so neither patient was operated on, but both were followed-up conservatively. We reviewed 51 cases of LIH. The patient's ages ranged from 4 to 74 years (mean 45.4 years). Based on the initial symptoms, DI was found in all cases. Almost all these cases revealed characteristic MRI findings similar to those in our cases. The mean follow-up period was 3.1 years. The rate of disappearance of radiological abnormalities was 56.2%, but only 13.7% of DI improved. If we encounter a patient presenting with idiopathic DI whose MRI is strongly suggestive of LIH, and barring the necessity of an urgent operation, careful conservative treatment is advised.

[Progressive brain injury].

The aim of this study was to evaluate the clinical manifestations and prognostic factors of progressive brain injury following trauma. We reviewed the records of 779 patients with head injury who had an admission Glasgow Coma Scale of 9 or more; 70 (7.0%) developed progressive brain injury as evidenced on serial CT scans. Of these 70 patients, 19 (27.1%) had a subdural hematoma, 19 (27.1%) an epidural hematoma, 16 (22.9%) a cerebral contusion, 13 (18.6%) an intracerebral hematoma, and 3 (4.3%) a diffuse brain swelling. Three months after injury, 36 (51.4%) patients died, 2 (2.9%) were left in a vegetative state and 23 (32.9%) had a favorable outcome. The appearance of progressive brain injury was associated with patient age, admission Glasgow Coma Scale, injury mechanisms, skull fracture and hemorrhagic lesions on the initial CT scan. Patients with the extracerebral lesions deteriorated 4 hours after injury, whereas those with intracerebral lesions deteriorated 8 hours after injury. The outcome based on Glasgow Outcome Scale was significantly associated with age, type of intracranial lesion, Glasgow Coma Scale following deterioration, the mechanism of injury and surgical treatment. It is concluded that early repeated CT scan is indicated in patients with risk factors of developing progressive brain injury.

[Solitary fibrous tumor of the fourth ventricle: case report].

A rare case of solitary fibrous tumor, located wholly within the fourth ventricle, is reported. A 57-year-old male presented with headache and nausea. The preoperative magnetic resonance images revealed a well circumscribed mass in the fourth ventricle that exhibited a low intensity on T1-weighted images and homogeneously enhanced with gadolinium. Vertebral angiogram revealed a tumor stain supplied from the choroidal branches of the posterior inferior cerebellar artery. The tumor was totally resected through a midline suboccipital approach. Histologically, the tumor was composed of spindle-shaped cells growing in fascicles within a collagenous matrix. Immunohistochemical staining demonstrated vimentin and the CD34 positivity of tumor cells. Solitary fibrous tumor is a newly described entity, which should be considered in the differential diagnosis for dural-based lesions.