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Hemorrhagic transformation upon reperfusion therapy has focused attention on ischemia-induced endothelial dysfunction. This study examined whether hyperglycemia may induce hemorrhagic transformation by enhancing endothelial mitochondrial damage during ischemia and whether preconditioning (PC) stimuli may limit ischemia-induced endothelial damage. In vivo, rats received 2.8 M D-glucose or arabinose (1 ml/100 g; i.p.) prior to undergoing two hours of middle cerebral artery occlusion and transcardiac fixation for electron microscopy. In vitro, brain endothelial cells were exposed to a PC impulse (short-term oxygen glucose deprivation; OGD) prior to an injurious event (5 hours OGD). Endothelial injury was assessed by measuring lactate dehydrogenase release. Hyperglycemia during cerebral ischemia resulted in marked changes in endothelial morphology and mitochondrial swelling. Thus, in the ischemic hemisphere, there was no evidence of endothelial mitochondrial swelling in normoglycemic rats (mean profile width 0.22 ± 0.04 vs. 0.17 ± 0.01 µm in contralateral hemisphere) but there was marked swelling in hyperglycemic rats (0.44 ± 0.02 µm). In vitro, cells preconditioned with one hour of OGD one day prior to 5 hours of OGD, showed reduced lactate dehydrogenase release (p < 0.05). In conclusion, hyperglycemia may have specific adverse effects on endothelial cell mitochondria during ischemia. Preventing those effects may help to ameliorate blood-brain barrier disruption on reperfusion. Insights into how to prevent endothelial injury may come from determining the mechanisms involved in endothelial preconditioning.

Our previous studies showed that intracerebral infusion of argatroban, a specific thrombin inhibitor, reduces brain edema and neurological deficits in a C6 glioma model. The present study investigated whether systemic argatroban administration can reduce glioma mass and neurological deficits and extend survival time in C6 and F98 gliomas. Rat C6 or F98 glioma cells were infused into the right caudate of adult male Fischer 344 rats. Osmotic minipump loaded with argatroban (0.3 mg/hour) or vehicle was implanted into abdomen immediately after glioma implantation. Tumor mass was determined at day 9. Over the period of the experiment, the animals underwent behavioral testing (forelimb placing and forelimb use asymmetry). In addition, survival time was tested in the F98 glioma model. In C6 glioma, argatroban reduced glioma mass (p < 0.05) and neurological deficits (p < 0.05) at day 9. In F98 glioma, agratroban prolonged the survival time (p < 0.05) and reduced the body weight loss (84 ± 15 gram vs. 99 ± 2 gram in the vehicle group, P < 0.05). In conclusion, systemic use of argatroban reduced tumor mass and neurological deficits, and prolonged survival time. These results suggest that thrombin plays a key role in glioma growth and thrombin inhibition with argatroban may be a novel treatment for gliomas.

Intracerebral hemorrhage (ICH) induces brain edema formation via a variety of mechanisms including toxicity due to thrombin and erythrocyte lysis. However, the roles of oxidative damage and excitotoxicity have not been fully elucidated and they are examined in this rat ICH study. Adult male Sprague-Dawley rats received an intracaudate injection of 100 µl autologous whole blood and 5 U of thrombin. Rats were sacrificed at 1 hour, 1 and 3 days, and then the brains processed using Western blotting to quantify N-methyl- D-aspartate receptor (NR) subunit expression. At 3 days, animals were also sacrificed for assessment of protein oxidation using Western blot analysis for dinitrophenyl (DNP) and brain water content. Compared to the contralateral side, ipsilateral basal ganglia NR1 and NR2A subunit expression transiently increased at 1 hour after ICH and thrombin injection. From 24 hours there was a marked down-regulation. At 3 days, marked edema and DNP up-regulation were observed in ICH and thrombin injection groups. The present NR expression up-regulation at 1 hour may reflect the acute cell response after ICH. The down-regulation of NR subunits and up-regulation of DNP may be associated with cell damage, towards which thrombin may contribute.

Age is an important factor affecting oxidative stress and plasticity after brain injury. The present study investigated the effects of aging on brain injury after intracerebral hemorrhage (ICH). Aging (18- month) and young (3-month) male Sprague-Dawley rats received an intracerebral infusion of 100-µl autologous blood. Age-related changes in brain edema and neurological deficits were examined and heat shock protein 27 (HSP27) and heat shock protein 32 (HSP32) levels were determined by Western blotting. Perihematomal brain swelling was more severe in aged rats compared to young rats at three days after ICH (P < 0.05). The behavioral tests used were forelimb placing test and forelimb use asymmetry test. There were more severe neurological deficits and a slower recovery in aged rats compared to those in young rats after ICH (P < 0.05). In addition, perihematomal HSP27 and HSP32 protein levels were higher (p < 0.05) in aged rats. In conclusion, ICH causes more severe brain swelling and neurological deficits in aged rats. Clarification of the mechanisms of brain injury after ICH in the aging brain should help develop new therapeutic strategies for hemorrhagic brain injury.

N-acethylcysteine (NAC) is known to have direct and indirect antioxidant abilities. We investigated the potential protective effect of NAC on ICP, brain edema and contusion volume after Controlled Cortical Impact (CCI) injury. A moderate CCI injury was induced on the left hemisphere in 48 Sprague Dawley rats. The animals were treated with intraperitoneal injection of NAC (163 mg/kg/KG) or physiological saline. Measurements of intracranial pressure (ICP) were performed and brains were removed at 24 hours. Gravimetric analysis of post-traumatic edema and morphometric measurements (TTC staining) of contusion volume were carried out in 24 animals, respectively. ICP measurements increased significantly over time with no significant differences between both groups. The relative difference in water content in NAC treated animals (1.45 ± 0.1%) did not differ significantly versus placebo (1.47 ± 0.2%). The contusion volume was diminished by 19% in the NAC group (53.52 ± 5.3 mm) versus placebo (66.28 ± 4.7 mm) without showing statistical significance. The antioxidant properties of NAC did not affect intracranial pressure or posttraumatic brain edema formation, although the moderate reduction of contusion volume might reveal beneficial effects on focal contusion.

Freud first proposed the concept of secondary gain, which he described as “… interpersonal or social advantage attained by the patient as a consequence of … illness” (Freud, 1917). This is to be differentiated from primary gain, an intrapsychic phenomenon by which anxiety is reduced through an unconscious defensive operation resulting in symptoms of a physical illness. Blindness or limb paralysis for which a medical etiology cannot be demonstrated are examples of symptoms of illness mediated by primary gain. Ultimately, the psychiatric diagnosis of “hysteria,” a somatoform conversion disorder, may be made in these patients.