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R. Loch Macdonald, Bryce Weir, John Zhang, Linda S. Marton, Michael Sajdak and Lydia M. Johns

Adenosine triphosphate (ATP) is a vasoactive compound found in high levels inside erythrocytes that may contribute to vasospasm occurring after subarachnoid hemorrhage (SAH). This study was instituted to test whether ATP causes vasospasm in a monkey model.

Thirty-two monkeys were randomized to four groups of eight monkeys each to undergo cerebral angiography at baseline (Day 0) and then at Day 7 after subarachnoid placement of: 1) agarose, 2) ATP in agarose, 3) autologous hemolysate in agarose, or 4) purified human hemoglobin A0 in agarose. Vasospasm was assessed by comparison of Day 0 and Day 7 angiograms between and within groups and by pathological examination of a subset of perfusion-fixed monkeys. Levels of adenine nucleotides were measured on Day 7 in subarachnoid agarose by high-pressure liquid chromatography.

There was significant vasospasm of the right middle cerebral artery in groups given ATP (-28 ± 7% reduction, paired t-test, p < 0.05), hemolysate (-23 ± 7%, p < 0.05), or pure hemoglobin (-15 ± 2%, p < 0.005). Analysis of variance revealed no significant differences between groups in diameters of cerebral arteries on Day 7. Pathological examination showed mild inflammation in the subarachnoid spaces of animals exposed to hemolysate or hemoglobin and less inflammation in those given ATP or agarose. There were no pathological changes in the cerebral arteries of animals in any group. Most of the ATP diffused out of the subarachnoid agarose by Day 7, and levels of adenine nucleotides in subarachnoid agarose were higher on Day 7 in animals exposed to hemoglobin or hemolysate.

It is concluded that ATP could contribute to vasospasm occurring after SAH but that further investigations are necessary to determine if levels of ATP adjacent to vasospastic arteries are sufficient to contribute to vasospasm. In addition, no observation was made of severe vasospasm with histopathological changes in the arteries equivalent to that produced by whole blood clot in the subarachnoid space of monkeys. It should be determined whether this is because a single compound, such as ATP or hemoglobin, causes vasospasm, but that placing the compound in agarose alters its delivery and decreases the amount of vasospasm produced, or whether vasospasm is a more complex, multifactorial process.

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Donald Seyfried, Yuxia Han, Zhang Zheng, Nancy Day, Kamiar Moin, Sandra Rempel, Bonnie Sloane and Michael Chopp

✓ Lysosomal proteases, although tightly regulated under physiological conditions, are known to contribute to cell injury after various forms of tissue ischemia have occurred. Because cathepsin B is a prominent lysosomal protease found in brain parenchyma, the authors hypothesized that it may contribute to neuronal cell death after focal cerebral ischemia. The authors measured the expression and spatial distribution of cathepsin B within the ischemic brain in 43 animals by means of immunohistochemical analysis in a rat model of transient middle cerebral artery (MCA) occlusion. Cathepsin B activity was also measured within specific ischemic brain regions by using an in vitro assay (22 animals). In addition, the authors tested the therapeutic effect of preischemic intraventricular administration of stefin A, a cysteine protease inhibitor, on the volume of cerebral infarction after transient MCA occlusion (15 animals). Increased cathepsin B immunoreactivity was detected exclusively within the ischemic neurons after 2 hours of reperfusion following a 2-hour MCA occlusion. Cathepsin B immunolocalization in the ischemic region decreased by 24 hours of reperfusion, but then increased by 48 hours of reperfusion because the infarct was infiltrated by inflammatory cells. Increased immunolocalization of cathepsin B in the inflammatory cells located in the necrotic infarct core continued through 7 days of reperfusion. Cathepsin B enzymatic activity was significantly increased in the ischemic tissue at 2, 8, and 48 hours, but not at 24 hours of reperfusion after 2 hours of MCA occlusion. Continuous intraventricular infusion of stefin A, before 2 hours of MCA occlusion (15 animals), significantly reduced infarct volume compared with control animals (12 animals): the percentage of hemispheric infarct volume was 20 ± 3.9 compared with 33 ± 3.5 (standard error of the mean; p = 0.025). These data indicate that neuronal cathepsin B undergoes increased expression and activation within 2 hours of reperfusion after a 2-hour MCA occlusion and may be a mechanism contributing to neuronal cell death. Intraventricular infusion of stefin A, an inhibitor of cathepsin B, significantly reduces cerebral infarct volume in rats.

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Hangjun Ruan, Lily Hu, Jingli Wang, Tomoko Ozawa, Nader Sanai, Michael Zhang, Kathleen R. Lamborn and Dennis F. Deen

Object

The presence of hypoxic cells in human brain tumors contributes to the resistance of these tumors to radiation therapy. However, because normal tissues are not hypoxic, the presence of hypoxic cells also provides the potential for designing cancer-specific gene therapy. Suicide genes can be expressed specifically in hypoxic conditions by hypoxia-responsive elements (HREs), which are activated through the transcriptional complex hypoxia-inducible factor–1 (HIF-1).

Methods

The authors have transfected the murine BAX–green fluorescent protein (GFP) fusion gene under the regulation of three copies of HRE into U-87 MG and U-251 MG cells and selected stably transfected clones. Even though BAX was expressed under both oxic and anoxic conditions in these clones, cell survival assays demonstrated increased cell killing under anoxic as compared with oxic conditions. Cells obtained from most of these clones did not grow in vivo, or the tumors exhibited highly variable growth rates. However, cells obtained from the U-251 MG clone A produced tumors that grew as well as tumors derived from parental cells, and examination of the tumor sections under fluorescent microscopy revealed GFP expression in localized regions. Western blot analyses confirmed an increased BAX expression in these tumors. Analysis of the results suggests that HRE-regulated BAX can be a promising tool to target hypoxic brain tumor cells. However, there are measurable levels of BAX-GFP expression in this three-copy HRE–mediated expression system under oxia, suggesting promoter leakage. In addition, most clones did not show significant induction of BAX-GFP under anoxia. Therefore, the parameters of this HRE-mediated expression system, including HRE copy number and the basal promoter, need to be optimized to produce preferential and predictable gene expression in hypoxic cells.

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Dunyue Lu, Asim Mahmood, Ruilan Zhang, Yi Li and Michael Chopp

Object. Neurogenesis, which is upregulated by neural injury in the adult mammalian brain, may be involved in the repair of the injured brain and functional recovery. Therefore, the authors sought to identify agents that can enhance neurogenesis after brain injury, and they report that (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA/NONOate), a nitric oxide donor, upregulates neurogenesis and reduces functional deficits after traumatic brain injury (TBI) in rats.

Methods. The agent DETA/NONOate (0.4 mg/kg) was injected intraperitoneally into 16 rats daily for 7 days, starting 1 day after TBI induced by controlled cortical impact. Bromodeoxyuridine (100 mg/kg) was also injected intraperitoneally daily for 14 days after TBI to label the newly generated cells in the brain. A neurological functional evaluation was performed in all rats and the animals were killed at 14 or 42 days postinjury. Immunohistochemical staining was used to identify proliferating cells.

Conclusions. Compared with control rats, the proliferation, survival, migration and differentiation of neural progenitor cells were all significantly enhanced in the hippocampus, subventricular zone, striatum, corpus callosum, and the boundary zone of the injured cortex, as well as in the contralateral hemisphere in rats with TBI that received DETA/NONOate treatment. Neurological functional outcomes in the DETA/NONOate-treated group were also significantly improved compared with the untreated group. These data indicate that DETA/NONOate may be useful in the treatment of TBI.

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Dunyue Lu, Asim Mahmood, Anton Goussev, Timothy Schallert, Changsheng Qu, Zheng Gang Zhang, Yi Li, Mei Lu and Michael Chopp

Object. Atorvastatin, a β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitor, has pleiotropic effects, such as promoting angiogenesis, increasing fibrinolysis, and reducing inflammatory responses, and has shown promise in enhancing recovery in animals with traumatic brain injury (TBI) and stroke. The authors tested the effect of atorvastatin on vascular changes after TBI.

Methods. Male Wistar rats subjected to controlled cortical impact injury were perfused at different time points with fluorescein isothiocyanate (FITC)—conjugated dextran 1 minute before being killed. Spatial memory function had been measured using a Morris Water Maze test at various points before and after TBI. The temporal profile of intravascular thrombosis and vascular changes was measured on brain tissue sections by using a microcomputer imaging device and a laser confocal microscopy. The study revealed the following results. 1) Vessels in the lesion boundary zone and hippocampal CA3 region showed a variety of damage, morphological alterations, reduced perfusion, and intraluminal microthrombin formation. 2) Atorvastatin enhanced FITC—dextran perfusion of vessels and reduced intravascular coagulation. 3) Atorvastatin promoted the restoration of spatial memory function.

Conclusions. These results indicated that atorvastatin warrants investigation as a potential therapeutic drug for TBI.

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J Mocco, William J. Mack, Andrew F. Ducruet, Ryan G. King, Michael E. Sughrue, Alexander L. Coon, Sergei A. Sosunov, Robert R. Sciacca, Yuan Zhang, Henry C. Marsh Jr., David J. Pinsky and E. Sander Connolly Jr.

Object

Postischemic cerebral inflammatory injury has been extensively investigated in an effort to develop effective neuroprotective agents. The complement cascade has emerged as an important contributor to postischemic neuronal injury. Soluble complement receptor Type 1 (sCR1), a potent inhibitor of complement activation, has been shown to reduce infarct volume and improve functional outcome after murine stroke. Given numerous high-profile failures to translate promising antiinflammatory strategies from the laboratory to the clinic and given the known species-specificity of the complement cascade, the authors sought to evaluate the neuroprotective effect of sCR1 in a nonhuman primate model of stroke.

Methods

A total of 48 adult male baboons (Papio anubis) were randomly assigned to receive 15 mg/kg of sCR1 or vehicle. The animals were subjected to 75 minutes of middle cerebral artery occlusion/reperfusion. Perioperative blood samples were analyzed for total complement activity by using a CH50 assay. Infarct volume and neurological scores were assessed at the time the animals were killed, and immunohistochemistry was used to determine cerebral drug penetration and C1q deposition. An interim futility analysis led to termination of the trial after study of 12 animals. Total serum complement activity was significantly depressed in the sCR1-treated animals compared with the controls. Immunostaining also demonstrated sCR1 deposition in the ischemic hemispheres of treated animals. Despite these findings, there were no significant differences in infarct volume or neurological score between the sCR1- and vehicle-treated cohorts.

Conclusions

A preischemic bolus infusion of sCR1, the most effective means of administration in mice, was not neuroprotective in a primate model. This study illustrates the utility of a translational primate model of stroke in the assessment of promising antiischemic agents prior to implementation of large-scale clinical trials.

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Asim Mahmood, Dunyue Lu, Changsheng Qu, Anton Goussev, Zheng Gang Zhang, Chang Lu and Michael Chopp

Object

This study was designed to investigate the neuroprotective properties of recombinant erythropoietin (EPO) and carbamylated erythropoietin (CEPO) administered following traumatic brain injury (TBI) in rats.

Methods

Sixty adult male Wistar rats were injured with controlled cortical impact, and then EPO, CEPO, or a placebo (phosphate-buffered saline) was injected intraperitoneally. These injections were performed either 6 or 24 hours after TBI. To label newly regenerating cells, bromodeoxyuridine was injected intraperitoneally for 14 days after TBI. Blood samples were obtained on Days 1, 2, 3, 7, 14, and 35 to measure hematocrit. Spatial learning was tested using the Morris water maze. All rats were killed 35 days after TBI. Brain sections were immunostained as well as processed for the enzyme-linked immunosorbent assay to measure brain-derived neurotrophic factor (BDNF).

Results

A statistically significant improvement in spatial learning was seen in rats treated with either EPO or CEPO 6 or 24 hours after TBI (p < 0.05); there was no difference in the effects of EPO and CEPO. Also, these drugs were equally effective in increasing the number of newly proliferating cells within the dentate gyrus at both time points. A statistically significant increase in BDNF expression was seen in animals treated with both EPO derivatives at 6 or 24 hours after TBI. Systemic hematocrit was significantly increased at 48 hours and 1 and 2 weeks after treatment with EPO but not with CEPO.

Conclusions

These data demonstrate that at the doses used, EPO and CEPO are equally effective in enhancing spatial learning and promoting neural plasticity after TBI.

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Aaron S. Dumont, Avery J. Evans and Mary E. Jensen

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Luis M. Tumialán, Y. Jonathan Zhang, C. Michael Cawley, Jacques E. Dion, Frank C. Tong and Daniel L. Barrow

Object

The introduction of the Neuroform microstent has facilitated the embolization of complex cerebral aneurysms, which were previously not amenable to endovascular therapy. Typically, the use of this stent necessitates the administration of dual antiplatelet therapy to minimize thromboembolic complications. Such therapy may increase the risk of hemorrhage in patients who require concurrent external ventricular drainage and/or subsequent permanent cerebrospinal fluid diversion.

Methods

The authors' neurosurgical database was queried for all patients who underwent stent-assisted coil embolization for cerebral aneurysms and who required an external ventricular drain (EVD) or ventriculoperitoneal (VP) shunt placement for management of hydrocephalus.

Results

Thirty-seven patients underwent stent-assisted coil embolization for intracranial aneurysms at the authors' institution over a recent 2-year period. Seven of these patients required placement of an EVD and/or a VP shunt. Three of the 7 patients suffered an immediate intraventricular hemorrhage (IVH) associated with placement or manipulation of an EVD; 1 experienced a delayed intraparenchymal hemorrhage and an IVH; 1 suffered an aneurysmal rehemorrhage; and the last patient had a subdural hematoma (SDH) that resulted from placement of a VP shunt. This patient required drainage of the SDH and exchange of the valve.

Conclusions

The necessity of dual antiplatelet therapy in the use of stent-assisted coil embolization increases the risk of intracranial hemorrhage and possibly rebleeding from a ruptured aneurysm. This heightened risk must be recognized when contemplating the appropriate therapy for a cerebral aneurysm and when considering the placement or manipulation of a ventricular catheter in a patient receiving dual antiplatelet therapy. Further study of intracranial procedures in patients receiving dual antiplatelet therapy is indicated.

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Kai Zhang, Sanjay Bhatia, Michael Y. Oh, David Cohen, Cindy Angle and Donald Whiting

Object

Deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus (VIM) has proven to be efficacious in the treatment of essential tremor (ET). The authors report on long-term follow-up of a series of patients treated at 1 institution by 1 neurosurgeon.

Methods

Thirty-four patients with ET received unilateral or bilateral VIM DBS. The tremor and handwriting components of the Fahn-Tolosa-Marin clinical tremor rating scale were assessed pre- and postoperatively. Visual analog scale scores for overall patient satisfaction and tremor control were recorded. Stimulation parameters at different intervals after surgery were also recorded.

Results

The average follow-up period was 56.9 months. The average tremor score improved from 3.27 preoperatively to 0.64 postoperatively (on stimulation; p < 0.001) and the average handwriting score improved from 2.94 to 0.89 (p < 0.001). The average visual analog scale score for overall satisfaction was 8.12 and for tremor control was 1.43. Overall, there was an 80.4% improvement in tremor and 69.7% improvement in handwriting. In 12 patients both tremor and handwriting scores were compared between 57.3 months and 90.7 months after surgery and no significant changes were discovered. Comparison of stimulation parameters at onset and at 1–3, 3–5, 5–7, and > 7 years after surgery showed significant differences, with a gradual increase in stimulation parameters within 5 years after surgery. The overall hardware-related complication rate was 23.5%.

Conclusions

Deep brain stimulation of the VIM is an efficient and safe treatment for ET. Tremor and handwriting improvements in long-term follow-up are stable. The patients' perception of their outcome is quite good. However, tolerance may develop in some patients requiring changes in stimulation parameters.