Hemispheric Swelling Research Articles

The Effects of Venous Ischaemia on the Subependymal and Choroid Plexus Morphology in Rat

Morphological changes of ependyma, subependyma and choroids plexus regions were evaluated after experimental anastomotic venous occlusion in twenty male Sprague-Dawley rats. In this model, small burr holes were made over the anterior and posterior anastomotic veins and after precisely locating these vessels, bipolar coagulation and microscissors were used to perform permanent occlusion. Three days later, rats were sacrificed by perfusion and fixation and specimens were evaluated by histopathological techniques. Morphological changes of ependymal, subependymal and choroids plexus cells were evaluated in operated and intact hemispheres and revealed cell proliferation in the subventricular zone adjacent to the territory of venous occlusion in the operated hemisphere as well as midline shift, brain oedema, subcortical petechial haemorrhage, brain infarction and hemispheric swelling. In conclusion, following anterior (the vein of Throlard) and posterior (the vein of Labbé) anastomotic vein occlusion, cell proliferation can be seen in the choroids plexus, ependymal and subependymal regions in rats. We conclude that these morphological changes might be part of a self-repairing mechanism in the brain.

A Model of Unilateral Cerebral Anterior and Posterior Anastomotic Vein Occlusion in the Rat

A new rat model of the sacrifice of the anterior and posterior cortical anastomotic veins by the microsurgical technique was used to evaluate venous infarction. 20 male Sprague-Dawley rats were used in this experiment. Small burr-holes were done over the anterior and posterior anastomotic veins. After the precise description of these vessels, bipolar coagulation and micro-scissor was used for sacrifice. Specimens were evaluated by histopathological techniques. Hemispheric swelling, midline shift, brain edema, subcortical petechial hemorrhage, infarction and necrosis were histopathological findings on the microscopic examination. Our results revealed that the sacrifice of the anterior and posterior anastomotic veins was a very successful model in the evaluation of brain damage after the disturbance to the venous circulation.

Characterization of a New Rat Model of Penetrating Ballistic Brain Injury

Penetrating brain injury (PBI) is a leading cause of mortality and morbidity in modern warfare and accounts for a significant number of traumatic brain injuries worldwide. Here we characterize the pathophysiology of a new rat model of PBI that simulates the large temporary cavity caused by energy dissipation from a penetrating bullet round. Male Sprague-Dawley rats (250-300 g) were subjected to a simulated ballistic wound to the right frontal hemisphere implemented by an inflatable penetrating probe. Three levels of injury severity were compared to control animals. Neurological and physiological outcome was assessed over a 3-day recovery period and brain tissue collected at 72 h for histopathological evaluation. Brain-injured regions included the ipsilateral frontal cortex and striatum with volumetric increases in intracranial hemorrhage (5-18 mm3) and lesion size (9-86 mm3) related to severity. Similarly, hemispheric swelling increased (3-14%) following PBI, associated with a significant rise in intracranial pressure. Astrogliosis was present in regions adjacent to the core-injury along with microglial and leukocyte infiltration. Injury remote to the lesion was observed in the cerebral peduncle that may have accounted, in part, for observed neurological deficits. Neurological and balance beam testing revealed sensorimotor deficits that persisted through 72 h. Severe electroencephalographic disturbances included the occurrence of cortical spreading depression, slow-waves, and brain seizure activity. In conclusion, this rat PBI model replicates diverse, salient features of clinical PBI pathology, generates reproducible and quantifiable measures of outcome, and is scalable by injury severity, rendering it an attractive vehicle for experimental brain trauma research.

Ultra early transient brain swelling following brief intraoperative ischaemia-reperfusion.

We describe a 50-year-old patient who developed acute transient hemispheric cerebral swelling, documented by computed tomography, following a temporary constriction (20 min) of the middle cerebral artery branches due to clipping of an aneurysm. Reporting of this postischaemic phenomenon has been limited and its mechanism and treatment remain unclear. A possible underlying process could be a postischaemic reactive vasodilatation leading to congestive hyperaemia. Hyperventilation and mannitol seem to be an effective treatment of this essentially 'benign' cerebral swelling. Copyright 1999 Harcourt Publishers Ltd.

Sodium 4-phenylbutyrate protects against cerebral ischemic injury.

Sodium 4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid that has been used for treatment of urea cycle disorders in children, sickle cell disease, and thalassemia. It has been demonstrated recently that 4-PBA can act as a chemical chaperone by reducing the load of mutant or mislocated proteins retained in the endoplasmic reticulum (ER) under conditions associated with cystic fibrosis and liver injury. In the present study, we evaluated the neuroprotective effect of 4-PBA on cerebral ischemic injury. Pre- or post-treatment with 4-PBA at therapeutic doses attenuated infarction volume, hemispheric swelling, and apoptosis and improved neurological status in a mouse model of hypoxia-ischemia. Moreover, 4-PBA suppressed ER-mediated apoptosis by inhibiting eukaryotic initiation factor 2alpha phosphorylation, CCAAT/enhancer-binding protein homologous protein induction, and caspase-12 activation. In neuroblastoma neuro2a cells, 4-PBA reduced caspase-12 activation, DNA fragmentation, and cell death induced by hypoxia/reoxygenation. It protected against ER stress-induced but not mitochondria-mediated cell death. Additionally, 4-PBA inhibited the expression of inducible nitric-oxide synthase and tumor necrosis factor-alpha in primary cultured glial cells under hypoxia/reoxygenation. These results indicate that 4-PBA could protect against cerebral ischemia through inhibition of ER stress-mediated apoptosis and inflammation. Therefore, the multiple actions of 4-PBA may provide a strong effect in treatment of cerebral ischemia, and its use as a chemical chaperone would provide a novel approach for the treatment of stroke.

Edaravone protects against hypoxia/ischemia-induced endoplasmic reticulum dysfunction.

Endoplasmic reticulum (ER) stress-induced cell death plays an important role in cerebral ischemia. In the present study, we investigated whether edaravone (3-methyl-1-phenyl-pyrazolin-5-one), a free radical scavenger, can protect against ER damage induced by cerebral ischemia. In a mouse model of hypoxia/ischemia, treatment with edaravone reduced edema-corrected infarction volume, attenuated hemispheric swelling, and improved neurological status. Moreover, edaravone suppressed ER stress-mediated apoptosis by inhibiting eukaryotic initiation factor alpha phosphorylation, C/EBP homologous protein (CHOP) induction, and caspase-12 activation. In mouse primary cultured glial cells, edaravone attenuated ER stress as evidenced by inhibition of the induction of glucose regulated protein 78 and CHOP and XBP-1 splicing under treatment with tunicamycin (Tm), which induces ER stress. Tm did not induce the production of reactive oxygen species in primary cultured glial cells. In addition, the free radical scavengers N-acetyl-l-cysteine and ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] did not affect ER stress response caused by Tm. These results demonstrated a novel action of edaravone that can protect against ER dysfunction in cerebral ischemia.

Cerebral swelling in severe hyponatremia caused by water intoxication in a schizophrenic patient

A 41-year-old female suffering from water intoxication showing consciousness disturbance with a serum sodium level of 104 mEq/l followed by repeated seizures is reported. She had been treated for 16 years with the drug, chlorpromazine. The computed tomography (CT) showed a bilateral hemispheric swelling. This swelling improved after spontaneous urination with an amount of 6700 ml within the first 12 h. We postulate that severe hyponatremia is possibly life-threatening, moreover, it is hardly recognized if the past history or previous prescription record was not known, because the CT appearance is sometimes misinterpreted.

Noninvasive quantification of brain edema and the space-occupying effect in rat stroke models using magnetic resonance imaging.

Brain edema is a life-threatening consequence of stroke and leads to an extension of the affected tissue. The space-occupying effect due to brain edema can be quantified in rat stroke models with the use of MRI. The present study was performed to test 2 hypotheses: (1) Can quantification of the space-occupying effect due to brain edema serve as a noninvasive measure for brain water content? (2) Does morphometric assessment of brain swelling allow determination of true infarct size on MRI after correction for the space-occupying effect of edema? Thirty rats were subjected to permanent suture middle cerebral artery occlusion. MRI was performed after 6 or 24 hours, and hemispheric swelling was assessed morphometrically. Interobserver and intraobserver agreements were determined for MRI measurements. In study I, the space-occupying effect due to brain edema was correlated with the absolute brain water content by the wet/dry method. In study II, lesion volumes corrected and uncorrected for edema were calculated on MRI and on TTC staining and compared. Interobserver and intraobserver agreements for MRI measurements were excellent (r>or=0.97). Brain water content and hemispheric swelling correlated well after 6 and 24 hours (r>or=0.95). Corrected lesion volumes correlated with r=0.78 between TTC staining and MRI. Without edema correction, lesion volumes were overestimated by 20.3% after 6 hours and by 29.6% after 24 hours of ischemia. Morphometric assessment of hemispheric swelling on MRI can determine the increase in absolute brain water content noninvasively and can also provide ischemic lesion volumes corrected for brain edema.

Effects of early and late intravenous norepinephrine infusion on cerebral perfusion, microcirculation, brain-tissue oxygenation, and edema formation in brain-injured rats.

Reduction of cerebral perfusion during the early phase after traumatic brain injury is followed by a later phase of normal to increased perfusion. Thus, pharmacologically elevating mean arterial blood pressure with the aim of improving cerebral perfusion may exert different time-dependent effects on cortical perfusion, microcirculation, tissue oxygenation and brain edema formation after traumatic brain injury. Randomized, placebo-controlled trial. Experimental laboratory at a university hospital. A total of 37 male Sprague-Dawley rats subjected to a focal cortical contusion. At 4 or 24 hrs after focal traumatic brain injury, mean arterial blood pressure was increased to 120 mm Hg for 90 mins by infusing norepinephrine. In rats receiving physiologic saline, mean arterial blood pressure remained unchanged. In the first series, pericontusional cortical perfusion was measured using the laser Doppler flowmetry scanning technique before injury and before, during, and after the infusion period. In a second series, intracranial and cerebral perfusion pressure and intraparenchymal perfusion and tissue oxygen measured within the contused and pericontusional cortex were recorded continuously before, during, and after norepinephrine infusion. Changes in cortical microcirculation were investigated by orthogonal polarization spectral imaging. At the end of each experiment, hemispheric swelling and water content were determined gravimetrically. At 4 and 24 hrs after traumatic brain injury, intravenous norepinephrine significantly increased pericontusional cortical perfusion, which was also reflected by an increase in diameters and flow velocities of pericontusional arterioles and venules. Cerebral perfusion pressure and intraparenchymal perfusion and tissue oxygen were significantly increased during norepinephrine infusion at 4 and 24 hrs. Hemispheric swelling and water content showed no difference between the groups. After cortical impact injury, early and late intravenous norepinephrine infusion pressure-dependently increased cerebral perfusion and tissue oxygenation without aggravating or reducing brain edema formation. Future studies are warranted to determine long-term changes of short and prolonged norepinephrine-induced increases in mean arterial blood pressure and cerebral perfusion pressure.

Correlation of lesion volume and brain swelling from a focal brain trauma.

Brain edema and secondary growth of a traumatic brain tissue necrosis are important manifestations of secondary brain damage and of prognostic significance in severe head injury. Aim of the current study was to analyze the interdependency of the resulting brain swelling from the size of the focal traumatic lesion. Male Sprague-Dawley rats were intubated and mechanically ventilated. A trephination was made over the left parietal cortex for induction of a cold lesion. Different injury severities were achieved by varying the contact time of the cooled copper-cylinder and the exposed cortex. Animals were randomized into 12 experimental groups. Hemispheric brain swelling was measured in groups A1-A6 (n = 4-8) by gravimetry 24 hrs after lesions of six increasing severity levels. Correspondingly, in animals of groups B1-B6 (n = 5-7) the volume of necrosis was planimetrically assessed in histological serial sections of the brain obtained 24 hrs after trauma of different severity. In groups A1-A6. hemispheric brain swelling (increase in weight) was growing with increasing contact duration of the cold probe with the exposed cerebral cortex, i.e. from 7.7 +/- 0.4% (5 s) to a maximum of 9.9 +/- 0.5% (25 s). Longer contact periodes (30 s) were not further effective to increase hemispheric brain swelling. The contact times and extent of swelling were linearly correlated between 5 s and 25 s (r = 0.47; p < 0.01). The volume of necrosis in groups B1-B6 increased from 35.7 +/- 3.7 mm3 (5 s) to 106.3 +/- 10.3 mm3 (30 s). There was again a linear correlation between the duration of contact of the cold probe (i.e. injury severity) with the brain cortex and the volume of necrosis (r = 0.77; p < 0.01). Accordingly. the lesion volume could be increased in a reproducible manner from 35.7 up to 106.3 mm3 by extending the contact times of the cooling device and cerebral cortex. Hemispheric swelling, predominantly due to vasogenic brain edema, was expanding in relationship with the volume of necrosis.

Role of bradykinin B2 receptors in the formation of vasogenic brain edema in rats.

Bradykinin is a mediator of brain edema acting through B2 receptors. However, it is not known if bradykinin mediates the formation of cytotoxic or vasogenic brain swelling. To investigate this question we subjected rats to a cryogenic brain lesion over the left parietal cortex, a model well known to produce predominantly vasogenic brain edema. We inhibited bradykinin B2 receptors with the recently characterized nonpeptide B2 receptor antagonist, LF 16-0687. The animals were assigned to three groups (n = 10, each) receiving 10, or 100 microg/kg/min LF 16-0687 or vehicle (0.9% NaCl). Treatment started 15 min before trauma and was continued for 24 h. Another three groups of animals (n = 10, each) received 10 microg/kg/min LF 16-0687 starting 30 or 60 min after trauma or vehicle (0.9% NaCl) for 24 h. Animals were then sacrificed and swelling and water content of the brain were determined. In the vehicle treated group the traumatized hemisphere swelled by 9.3 +/- 1.1% as compared to the untraumatized contralateral side. Pretreatment with 10 microg/kg/min LF 16-0687 decreased brain swelling significantly to 6.4 +/- 1.3% (p < 0.05). Pre-treatment with 100 microg/kg/min was found to be less effective and did not result in a significant reduction of brain swelling (7.4 + 1.3%). Treatment with LF 16-0687 for 24 h (10 microg/kg/min) started 30 or 60 min after trauma did not reduce brain water content or hemispheric swelling. These results demonstrate that brain injury-mediated bradykinin production induces vasogenic brain edema by B2 receptor stimulation. Our findings further clarify the role of bradykinin in the pathophysiology of brain edema formation and confirm the therapeutic potency of bradykinin B2 receptor inhibition.

Neuroprotective effects of the CRF1 antagonist R121920 after permanent focal ischemia in the rat.

The neuroprotective effects of a systemically active, highly selective, corticotropin-releasing factor-1 (CRF1) receptor antagonist, R121920 ((7-(dipropylamino)-2,5-dimethyl-3- [2-(dimethylamino)-5-pyridyl] pyrazolo [1,5-a] pyrimidine), was assessed in two rat models of permanent focal cerebral ischemia, where the middle cerebral artery (MCA) was occluded either through the subtemporal approach or using the intraluminal suture technique. R121920 rapidly crossed the blood-brain barrier after intravenous (IV) bolus administration (10 mg/kg), with peak brain concentrations at 5 minutes (2.26 +/- 0.40 microg/mL), which were approximately 2-fold greater than those in plasma (0.98 +/- 0.24 microg/mL). Treatment with R121920 (10 mg/kg IV followed by 5 mg/kg subcutaneously at hourly intervals for 4 hours) significantly (P < 0.001) reduced total (by 40%) and cortical (by 37%) infarct volume at 24 hours after subtemporal MCA occlusion (MCAO). In the intraluminal suture MCAO model, IV administration of R121920 (10 mg/kg) at the time of ischemia onset (and at multiple times thereafter) reduced both hemispheric infarct volume (by 34%, P < 0.001) and brain swelling (by 50%, P < 0.001) when assessed at 24 hours. In this model of focal ischemia, significant reduction (P < 0.05) in both outcome measures was obtained when R121920 administration was delayed up to 1 hour after MCAO. These results further define the antiischemic properties of selective CRF 1 antagonists in two experimental models of permanent focal cerebral ischemia.

Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion

Insulin-like growth factor-I (IGF-I) has been proposed as a treatment for stroke. However, it does not efficiently cross the blood–brain barrier (BBB). Intracerebroventricular injection of IGF-I has been shown to offer protection against cerebral ischemic damage in rats although this invasive method of administration may not be practical in humans. Non-invasive intranasal (IN) delivery of IGF-I to the brain is a promising alternative. We have assessed the therapeutic effect of IN IGF-I in rats following middle cerebral artery occlusion (MCAO). Treatment was initiated 10 min after the onset of MCAO and then again 24 and 48 h later. Intranasal dosing of 75 μg IGF-1 (225 μg total IGF-I over 48 h) significantly reduced corrected infarct volumes by 60% vs. control ( P<0.01) and hemispheric swelling by 45.6% vs. control ( P<0.05). Neurologic function, assessed by the postural reflex, flexor response and adhesive tape tests, was also improved by IN IGF-I as compared to control. Our study indicates IN delivery of IGF-1 holds significant promise as a non-invasive and efficacious method of bypassing the BBB for the treatment of stroke.

Intranasal IGF-1 Protects against Transient Focal Cerebral Ischemia in Rats following Middle Cerebral Artery Occlusion (MCAO)

P71 Insulin-like growth factor-1 (IGF-1) has been shown to protect against stroke in rats when administered intracerebroventricularly. However, this administration method is not practical in humans as it requires surgery with the risk of infection. Intranasal (IN) delivery is a noninvasive method of bypassing the blood-brain barrier to deliver IGF-1 to the brain [Thorne et al. (1999) Growth Hormone and IGF Research 9: 387]. We have assessed the therapeutic potential of IN IGF-1 in rats following experimentally-induced focal cerebral ischemia and reperfusion. Rats were given a total of three 75 μg doses of IGF-1 (Chiron Corp.) IN over the course of the 72 hour study: 10 minutes after the onset of two hours of MCAO and then again 24 and 48 hours later. Five neurologic tests assessing motor, sensory, vestibulomotor and somatosensory functions were performed at 4, 24, 48 and 72 hours after the onset of MCAO under blinded conditions. Infarct volume, hemispheric swelling and pathological changes were evaluated at 72 hours after MCAO following euthanasia and coding for blind analysis. IGF-1 treatment significantly reduced the corrected infarct volume by 71 % (p=0.002) and hemispheric swelling by 37 % (p=0.017) when compared to vehicle-treated controls. In addition, the postural reflex and flexor response tests showed significant neurologic improvement with IGF-1 treatment (p=0.016 and 0.019 respectively). The adhesive-backed paper test showed borderline significance in both the contact and removal times (p=0.0573 and p=0.042 respectively). The forelimb placing and beam balance tests showed a clear recovery trend but did not reach statistical significance. While IGF-1 does not significantly cross the blood-brain barrier following traditional peripheral routes of administration, it can be delivered to the brain directly from the nasal cavity following intranasal administration. IN IGF-1 reduced both infarct volume and cerebral edema and also significantly reduced neurologic deficits following MCAO. Our study indicates IN delivery of IGF-1 holds significant promise as a noninvasive and efficacious method for treating stroke.

Neuroprotective effect of melatonin on cortical impact injury in the rat.

The pineal hormone melatonin is a highly efficient physiological scavenger of free radicals involved in secondary brain damage. A variety of experimental studies have demonstrated a neuroprotective effect for melatonin, based on its antioxidant activity. The purpose of the present study was to investigate the time-dependency and a possible protective effect of exogenous melatonin in the cortical impact model in rats. The protective effect was quantified determining contusion volume, brain edema and brain water content. 45 anesthetized male Sprague-Dawley rats (250-350 mg) were subjected to cortical impact injury of moderate severity (7 m/s, deformation 2 mm). Melatonin (100 mg/kg bw i.p.), or a vehicle was injected 20 min before trauma, immediately after, and 1 and 2 hours after trauma during daytime and nighttime. Posttraumatic lesion volume using hematoxylin-eosin staining, hemispheric swelling, brain water content, cerebral perfusion pressure and intracranial pressure 24 hours after injury were investigated. Melatonin, given during nighttime, significantly reduced contusion volume corresponding to a mean reduction of contusion volume of 27% (placebo, n = 7: 41.9 +/- 5.2 mm3, melatonin, n = 8: 30.5 +/- 4.2 mm3, p < 0.05). Given during daytime, the reduction in contusion volume was not significant (placebo, n = 8: 42.1 +/- 5.1 mm3, melatonin, n = 8: 35.9 +/- 2.2 mm3, reduction of 15%, p = 0.08, n.s.). Hemispheric swelling was unchanged by melatonin treatment. Mean arterial blood pressure and rectal temperature remained stable before and after the cortical impact injury and injection of melatonin. This study shows that melatonin significantly reduces contusion volume with major effects during night.

Effects of dopamine on posttraumatic cerebral blood flow, brain edema, and cerebrospinal fluid glutamate and hypoxanthine concentrations.

Dopamine is often used in the treatment of traumatic brain injury to maintain cerebral perfusion pressure. However, it remains unclear whether dopamine contributes to secondary brain injury caused by vasoconstriction and resulting diminished cerebral perfusion. The present study investigated the effects of dopamine in different concentrations on posttraumatic cortical cerebral blood flow (CBF), brain edema formation, and cerebrospinal fluid concentrations of glutamate and hypoxanthine. Randomized, placebo-controlled trial. Animal laboratory. Eighteen male Sprague-Dawley rats subjected to a focal cortical brain injury. Four hours after controlled cortical impact, rats were randomized to receive physiologic saline solution (n = 6), 10-12 tig/kg/min dopamine (n = 6), or 40-50 microg/kg/min dopamine (n = 6), for 3 hrs. Cortical CBF was measured over both hemispheres by using laser-Doppler flowmetry before trauma and before, during, and after the infusion period. At 8 hrs after trauma, brains were removed to determine hemispheric swelling and water content. Cisternal cerebrospinal fluid was sampled to measure glutamate and hypoxanthine. After trauma, cortical CBF was significantly decreased by 46% within the vicinity of the cortical contusion in all rats. Infusion of saline and 10-12 ig/kg/min dopamine did not change mean arterial blood pressure (MABP) or cortical CBF. However, infusion of 40-50 microg/kg/min dopamine, which elevated MABP from 89 to 120 mm Hg, significantly increased posttraumatic CBF within and around the contusion by 35%. Over the nontraumatized hemisphere, CBF remained unchanged. Hemispheric swelling, water content, cerebrospinal fluid glutamate, and hypoxanthine levels were not affected by dopamine in the given dosages. Under the present study design, there was no evidence for a dopamine-mediated vasoconstriction, because posttraumatic cortical CBF was increased by dopamine-induced elevation of MABP. However, the increase in CBF did not significantly affect edema formation or cerebrospinal fluid glutamate and hypoxanthine levels.

Riluzole reduces brain swelling and contusion volume in rats following controlled cortical impact injury.

Modulation of the glutamatergic and excitotoxic pathway may attenuate secondary damage following traumatic brain injury by reducing presynaptic glutamate release and blocking sodium channels in their inactivated state. The aim of the present study was to investigate the neuroprotective potential of riluzole in traumatic brain-injured rats. A left temporoparietal contusion was induced in 70 male Sprague-Dawley rats (controlled cortical impact injury). Riluzole (8 mg/kg body weight) was given 30 min, and 6, 24, and 30 h after trauma, while control rats received physiological saline. Experiments were performed at two different degrees of trauma severity as defined by penetration depth of the impactor rod (1 vs. 1.5 mm) with the aim of investigating impact of severity of tissue damage on the neuroprotective potential of riluzole. At 48 h after trauma, brains were removed to determine hemispheric swelling and water content and to assess cortical contusion volume. Before brain removal cisternal cerebrospinal fluid (CSF) was collected in all rats to determine the effects of riluzole on substances associated with edema formation. For this, the excitatory transmitter glutamate, the volume-regulatory amino acid taurine, and the ATP-degradation product hypoxanthine were analyzed by high-performance liquid chromatography. Overall, the degree of tissue damage seems to influence the neuroprotective potential of riluzole. In rats with a less severe trauma (1-mm penetration depth), hemispheric swelling, cerebral water content of the traumatized hemisphere and cortical contusion volume were significantly reduced under riluzole compared to controls (p < 0.05). In rats with a more severe trauma (1.5-mm penetration depth), the neuroprotective effect of riluzole failed to reach statistical significance. Following trauma, CSF glutamate, taurine, and hypoxanthine levels were significantly increased compared to nontraumatized rats (p < 0.001). However, these neurochemical parameters as measured in cisternal CSF failed to reflect trauma-dependent increases in severity of tissue damage and did not reveal riluzole-mediated neuroprotection. Under the present study design, riluzole significantly reduced brain edema formation and contusion volume in rats subjected to a mild focal cortical contusion.

LF16-0687 a novel non-peptide bradykinin B2 receptor antagonist reduces vasogenic brain edema from a focal lesion in rats.

Head injury world wide is still the most frequent cause of morbidity and mortality among the population under 45 years. Approximately 50% of patients dying from severe head injury have a therapy refractory intracranial pressure rise (Baethmann 1998). Traumatic brain edema, e.g. resulting from disruption of the blood-brain barrier is viewed as an important factor of the increased intracranial pressure. Bradykinin, an active peptide of the kallikrein-kinin system is considered to enhance brain edema formation which is attributed to its permeabilizing effect on the blood-brain barrier and on dilation of arterial blood vessels in the brain mediated by B2-receptors facilitating extravasation. Currently, LF16-0687, a novel non-peptide bradykinin B2 receptor antagonist was experimentally tested as to its therapeutical potential on vasogenic brain edema from a cortical focal lesion. Following trephination of the skull in anaesthesia, male Sprague-Dawley rats were subjected to a focal cold injury of the left parietal cortex. Animals of two experimental groups were receiving either LF16-0687 as high or low dose, whereas one group of untreated animals with trauma was treated with 0.9% NaCl as continuous infusion beginning 10 min before until 24 h after lesion. 24 h after trauma the brain was removed from the skull, and the cerebral hemispheres were separated in the median plane for gravimetric assessment of hemispheric swelling. No significant reduction of hemispheric brain swelling (+7.4 +/- 2.9%) was found in animals receiving high-dose LF16-0687 as compared to the untreated controls. Brain swelling, however was significantly attenuated by the low-dose treatment, i.e. to +6.4 +/- 1.3%; vs. +9.3 +/- 1.1% found in the controls, (p < 0.05). The current data confirm that blocking of bradykinin B2-receptors by LF16-0687 is significantly attenuating vasogenic brain edema from a focal cold lesion. The therapeutical properties of the antagonist on brain edema formation cannot be attributed to a lowering of the blood pressure. Rather, specific blocking effects of B2-receptors in the brain appear to be involved. In conclusion, the understanding of secondary brain damage including brain edema in head injury has been markedly enhanced by the discovery of pathophysiologically active mediator compounds playing a role in its various manifestations. The current data confirm a pathophysiological function of bradykinin in vasogenic brain edema mediated by activation of B2-receptors. Currently it is studied whether LF16-0687 also reduces brain swelling when given after an insult.

歯肉頬移行部に発生した筋上皮腫の１例

Myoepithelioma is a relatively rare benign salivary gland tumor that mainly occurs in the palatal or parotid glands. We encountered a rare case of this tumor in the gingivobuccal fold.The patient was a 54-year-old Japanese woman with a hemispherical globe-shape swelling. Computed tomography (CT) and ultrasonography showed a tumor in the gingivobuccal submucosa; there was no evidence of bone destruction. The tumor was surgically removed under the clinical diagnosis of a minor salivary gland tumor. Histologically, the tumor was composed mainly of plasmacytoid cells without malignant features. It was diagnosed as a myoepithelioma.In the Japanese literature, 15 cases of myoepithelioma, including our case, have been reported during the past 10 years. The most common sites were the parotid gland (5 cases, 33.3%) and palate (5 cases, 33.3%). To our knowledge, this is the first case of a myoepithelioma arising in the gingivobuccal fold to be reported in the Japanese literature.

Comparative neuroprotective efficacy of prolonged moderate intraischemic and postischemic hypothermia in focal cerebral ischemia.

The purpose of this study was to compare the effects of prolonged hypothermia on ischemic injury in a highly reproducible model of middle cerebral artery (MCA) occlusion in rats. Male Sprague-Dawley rats were anesthetized with halothane and subjected to 120 minutes of temporary MCA occlusion by retrograde insertion of an intraluminal nylon suture coated with poly-L-lysine through the external carotid artery into the internal carotid artery and the MCA. Two levels of prolonged postischemic cranial hypothermia (32 degrees C and 27 degrees C) and one level of intraischemic cranial hypothermia (32 degrees C) were compared with the ischemic normothermia (37 degrees C) condition. Target cranial temperatures were maintained for 3 hours and then gradually restored to 35 degrees C over an additional 2-hour period. The animals were evaluated using a quantitative neurobehavioral battery of tests before inducing MCA occlusion, during occlusion (at 60 minutes postonset in all rats except those in the intraischemic hypothermia group), and at 24, 48, and 72 hours after reperfusion. The rat brains were perfusion fixed at 72 hours after ischemia, and infarct volumes and brain edema were determined. Both intraischemic and postischemic cooling to 32 degrees C led to similar significant reductions in cortical infarct volume (by 89% and 88%, respectively) and total infarct volume (by 54% and 69%, respectively), whereas postischemic cooling to 27 degrees C produced lesser reductions (64% and 49%, respectively), which were not statistically significant. All three hypothermic regimens significantly lessened hemispheric swelling and improved the neurological score at 24 hours. The authors' data confirm that a high degree of histological neuroprotection is conferred by postischemic cooling to 32 degrees C, which is virtually equivalent to that observed with intraischemic cooling to the same level. These results may be relevant to the design of future clinical trials of therapeutic hypothermia for acute ischemic stroke.