The surgical brain injury model replicates neurosurgical brain parenchymal damage. Postsurgical brain edema correlates with postoperative neurological dysfunction. Intranasal administration is a proven method of delivering therapies to brain tissue. Thrombin preconditioning decreased brain edema and improved neurological outcomes in models of ischemic brain injury. We hypothesized thrombin preconditioning in surgical brain injury may improve postoperative brain edema and neurological outcomes. Adult male Sprague-Dawley rats (n = 78) weighing 285-355 g were randomly assigned to sham or pre-injury treatment: one-time pretreatment 1 day prior, one-time pretreatment 5 days prior, and daily preconditioning for 5 days prior. Treatment arms were divided into vehicle or thrombin therapies, and subdivided into intranasal (thrombin 5 units/50 μL 0.9 % saline) or intracerebral ventricular (thrombin 0.1 unit/10 μL 0.9 % saline) administration. Blinded observers performed neurological testing 24 h after brain injury followed immediately by measurement of brain water content. There was a significant difference in ipsilateral brain water content and neurological outcomes between all treatment groups and the sham group. However, there was no change in brain water content or neurological outcomes between thrombin- and vehicle-treated animals. Thrombin preconditioning did not significantly improve brain edema or neurological function in surgical brain injury in rats.

Neurosurgical procedures are associated with unintentional damage to the brain during surgery, known as surgically induced brain injuries (SBI), which have been implicated in orchestrating structural and neurobehavioral deterioration. Propofol, an established hypnotic anesthetic agent, has been shown to ameliorate neuronal injury when given after injury in a number of experimental brain studies. We tested the hypothesis that propofol pretreatment confers neuroprotection against SBI and will reduce cerebral edema formation and neurobehavioral deficits in our rat population. Sprague-Dawley rats were treated with low- and high-dose propofol 30 min before SBI. At 24 h post injury, brain water content and neurobehavioral assessment was conducted based on previously established models. In vehicle-treated rats, SBI resulted in significant cerebral edema and higher neurological deficit scores compared with sham-operated rats. Low- or high-dose propofol therapy neither reduced cerebral edema nor improved neurologic function. The results suggest that propofol pretreatment fails to provide neuroprotection in SBI rats. However, it is possible that a SBI model with less magnitude of injury or that propofol re-dosing, given the short-acting pharmacokinetic property of propofol, may be needed to provide definitive conclusions.

Neonatal hypoxia–ischemia (HI) is a devastating condition resulting in neuronal cell death and often culminates in neurological deficits. Granulocyte-colony stimulating factor (G-CSF) has been shown to have neuroprotective activity via inhibition of apoptosis and inflammation in various stroke models. Stem cell factor (SCF) regulates hematopoietic stem cells in the bone marrow and has been reported to have neuroprotective properties in an experimental ischemic stroke model. In this study, we aim to determine the protective effects of G-CSF in combination with SCF treatment after experimental HI. Seven-day-old Sprague–Dawley rats were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia. Animals were randomly assigned to five groups: Sham ( n = 8), Vehicle ( n = 8), HI with G-CSF treatment ( n = 9), HI with SCF treatment ( n = 9), and HI with G-CSF + SCF treatment (coadministration group; n = 10). G-CSF (50 μg/kg), SCF (50 μg/kg), and G-CSF + SCF (50 μg/kg) were administered intraperitoneally 1 h post HI followed by daily injection for 4 consecutive days (five total injections). Animals were euthanized 14 days after HI for neurological testing. Additionally, assessment of brain, heart, liver, spleen, and kidney atrophy was performed. Both G-CSF and G-CSF + SCF treatments improved body growth and decreased brain atrophy at 14 days post HI. No significant differences were found in the peripheral organ weights between groups. Finally, the G-CSF + SCF coadministration group showed significant improvement in neurological function. Our data suggest that administration of G-CSF in combination with SCF not only prevented brain atrophy but also significantly improved neurological function.

Attenuation of blood–brain barrier (BBB) disruption is one of the therapeutic candidates for treatment of subarachnoid hemorrhage (SAH). In this study, the protective effect of sodium orthovanadate (SOV) on BBB disruption was investigated in SAH using the endovascular perforation model. Fifty‐five rats were randomly assigned to sham‐operated, SAH treated with saline (as a vehicle), or 10 mg/kg SOV groups and were evaluated for neurofunction and Evans blue dye extravasation. The phosphorylation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and mitogen‐activated protein kinase (MAPK) and the expression of matrix metalloproteinase‐9 (MMP‐9), occludin, and collagen‐IV were examined by Western blot analyses. Cell death among endothelial cells was revealed by immunofluorescence and terminal deoxynucleotidyl transferase‐mediated uridine 5′‐triphosphate‐biotin nick end‐labeling staining. SOV significantly improved neurofunction and reduced Evans blue dye extravasation in brains after SAH. SOV phosphorylated PTEN, decreased phospho‐JNK and MMP‐9, and preserved occludin expression. SOV also attenuated SAH‐induced capillary endothelial cell death. The current study showed that SOV was protective against BBB disruption after SAH, possibly via PTEN phosphorylation. © 2011 Wiley Periodicals, Inc.

There is a growing understanding of cerebral amyloid angiopathy (CAA), which accounts for the majority of primary lobal intracerebral hemorrhages (ICH) among the elderly [1] and is cited as the cause of 20% of spontaneous ICHs in patients over 70 years of age [2]. The basis for this disease process is the deposition and formation of eventually destructive amyloid plaques in the walls of brain vessels, predominantly arterial but not excluding venules and capillaries [3]. Investigation of the pathophysiology and therapies for CAA-associated hemorrhages have been made possible through animal models utilizing species that develop CAA in a similar fashion to humans, such as the squirrel monkey, rhesus monkey, dog and mutant and transgenic mouse strains, which exhibit the age-related development of amyloid plaques, progressive neurodegeneration and CAA-associated hemorrhages. The disease course in these animal models resembles that seen in the clinical setting for patients with CAA. Rodent studies have been able to demonstrate the strong role of CAA and CAA-associated microhemorrhages in the pathogenesis and progression of CAA with and without AD [4]. This review will present the existing understanding of CAA-associated microhemorrhages frequently observed in AD, different animal models, involved imaging and the role of animal models in the development of therapeutics including immunotherapies such as anti-Aβ antibodies for the treatment of CAA and its associated microhemorrhages.

Objectives: As the population continues to live longer, the diagnosis of pituitary adenoma-induced apoplexy becomes more common in the elderly. The standard treatment options for pituitary apoplexy are debatable. Although there is little information regarding the treatment of pituitary apoplexy in elderly patients, the optimal treatment needs to be determined for this age group. The current study examined the surgical treatment of pituitary apoplexy in three patients over the age of 80. Case Description: Three patients over the age of 80 with pituitary apoplexy were admitted to our hospital. Some symptoms caused by pituitary apoplexy, including decreased visual acuity, double vision and oculomotor paresis, had persisted for more than 14 days. Magnetic resonance imaging revealed suprasellar mass lesions extending into the cavernous sinus. The general condition of the patients was good, and we performed endoscopic transsphenoidal surgery in each of these cases. The masses were removed, and the histological findings were diagnosed as non-functioning pituitary adenoma with presence of hemorrhagic or ischemic necrosis. Perioperative courses and general conditions were good, and the neurological deficits of each patient improved immediately. Conclusions: Endoscopic transsphenoidal surgery has the advantage of visualization of the structures surrounding the pituitary gland. Moreover, the complication rate is relatively low because stress on the pituitary gland can be reduced by using this procedure. Even in patients over 80 years of age during the subacute phase, endoscopic surgical management is a good treatment candidate for pituitary apoplexy with mass lesion extension into the cavernous sinus.

In order to understand a disease process, effective modeling is required that can assist scientists in understanding the pathophysiological processes that take place. Intracerebral hemorrhage (ICH), a devastating disease representing 15% of all stroke cases, is just one example of how scientists have developed models that can effectively mimic human clinical scenarios. Currently there are three models of hematoma injections that are being used to induce an ICH in subjects. They include the microballoon model introduced in 1987 by Dr. David Mendelow, the bacterial collagenase injection model introduced in 1990 by Dr. Gary Rosenberg, and the autologous blood injection model introduced by Dr. Guo-Yuan Yang in 1994. These models have been applied on various animal models beginning in 1963 with canines, followed by rats and rabbits in 1982, pigs in 1996, and mice just recently in 2003. In this review, we will explore in detail the various injection models and animal subjects that have been used to study the ICH process while comparing and analyzing the benefits and disadvantages of each.

Intracerebral hemorrhage (ICH) is the most devastating type of stroke. It is characterized by spontaneous bleeding in brain parenchyma and is associated with a high rate of morbidity and mortality. Presently, there is neither an effective therapy to increase survival after intracerebral hemorrhage nor a treatment to improve the quality of life for survivors. A reproducible animal model of spontaneous ICH mimicking the development of acute and delayed brain injury after ICH is an invaluable tool for improving our understanding of the underlying mechanisms of ICH-induced brain injury and evaluating potential therapeutic interventions. A number of models have been developed. While different species have been studied, rodents have become the most popular and widely utilized animals used in ICH research. The most often used methods for experimental induction of ICH are injection of bacterial collagenase and direct injection of blood into the brain parenchyma. The "balloon" method has also been used to mimic ICH for study. In this summary, we intend to provide a comparative overview of the technical methods, aspects, and pathologic findings of these types of ICH models. We will also focus on the similarities and differences among these rodent models, achievements in technical aspects of the ICH model, and discuss important aspects in selecting relevant models for study.

The neonatal hypoxia-ischemia rat model referred to as the Rice–Vannucci model is extensively used to study perinatal hypoxia-ischemia and child brain injury. One of the major weaknesses of this model is its inconsistency of brain infarction among animals. We hypothesize that the inconsistency of infarction is caused by prolonged operation time and therefore isoflurane exposure. Neonatal hypoxia-ischemia was induced in postnatal days 7 and 10 rat pups by unilateral right common carotid ligation followed by 2.5 h of hypoxia (8% oxygen). The incision-to-ligation (ITL) was defined as the amount of time from initial incision (4 min after 2% isoflurane exposure) to completion of carotid ligation (at which point isoflurane exposure was also terminated). In the first part of the study, the ITL of each group was designated to be 5, 13, and 21 min. In the second part of the study, the ITL is designated to 4 min; however, continued isoflurane was used to make 5, 13, and 21 min isoflurane exposure for each group. Percentages of brain infarction were assessed at 48 h following surgery. Motor deficits were accessed by Rotarod test. Marked brain infarction was observed in the 5-min ITL group and a decrease of brain infarction observed in the 13- and 21-min groups ( P < 0.05). In the second part of the study, marked brain infarction was observed in the 5-min isoflurane exposure group, and a decrease of brain infarction was observed in each of the 13- and 21-min isoflurane exposure groups ( P < 0.05). Similar tendencies were observed in Rotarod tests than 5-min ITL and 5-min isoflurane groups showed more marked deficits ( P < 0.05). This study demonstrated that brain infarction inconsistency of the neonatal hypoxia-ischemia rat pup model is related to the operation time. The observed time-dependent decrease of brain infarction is correlated to the isoflurane exposure time. Shorter operation and isoflurane exposure improves this model consistency of brain infarction and motor deficits.

AIMS:Intracerebral hemorrhage is one of the most devastating subtypes of stroke, leaving survivors with severe neurological deficits. Disruption of the blood brain barrier (BBB) following hemorrhage results in the development of vasogenic brain edema, a most life-threatening event after such events as intracerebral hemorrhage (ICH). The Evans Blue assay is a popular method for the quantification of BBB disruption. Although this method is in common use, there are several protocols of the assay in the literature which vary in the route of administration, as well as the circulation time of the stain. In this study, we compared the amounts of accumulated stain in brain tissue following intraperitoneal versus intravenous injection at 0.5, 3 and 24h of circulation time. METHODS:58 CD-1 mice were used. Animals were divided into ICH (N=42), sham groups (N=6) and naïve (N=10). ICH animals received stereotactic injection of collagenase type VII into the right basal ganglia. Sham animals received only needle trauma. Evans Blue stain was injected 24h after collagenase injection or needle trauma. The consistency of ICH produced was characterized by estimation of hematoma volume via hemoglobin assay and neurological evaluation. RESULTS:The produced hematoma and neurological deficits were well comparable between different experimental groups. There was no statistically significant difference in the results of the Evans Blue assay with regard to administration route. CONCLUSIONS:The amount of Evans Blue stain accumulated in the brains of mice after ICH produced by collagenase injection was independent of the stain administration route.

This study investigated the effect of geldanamycin post-treatment on the development of secondary brain injury and neurological deficits in a mouse model of intracerebral hemorrhage. CD-1 mice received stereotactic injection of collagenase type VII into the right basal ganglia. Treatment groups were administered 1 mg/kg (low dose) or 10 mg/kg (high dose) of geldanamycin. Mice were euthanized at two time-points: 24 h or 72 h. Blood-brain-barrier permeability, brain edema, and neurobehavioral deficits were assessed. Additionally, the effects of geldanamycin on heat shock protein 27 and 72; tumor necrosis factor-alpha and interleukin 1 beta expressions were evaluated.High dose geldanamycin significantly attenuated blood-brain barrier disruption and brain edema after intracerebral hemorrhage. Neurobehavioral outcomes were significantly improved in some parameters by high dose treatment. Molecular results showed a marked increase in heat shock protein 72 expression in ipsilateral brain of geldanamycin treated groups with a reduction in the proinflammatory tumor necrosis factor-alpha.Conclusion: Geldanamycin post-treatment is neuroprotective in the mouse model of intracerebral hemorrhage. Geldanamycin administration results in reduction of inflammation, preservation of blood-brain-barrier and amelioration of neurobehavioral deficits after an insult possibly by upregulation of heat shock protein 72. (C) 2010 Elsevier Ltd. All rights reserved.

The glutamatergic hypofunction hypothesis of schizophrenia has led to the development of novel therapeutic strategies modulating NMDA receptor function. One of these strategies targets the activation of the metabotropic glutamate receptor 5 (mGlu5 receptor) using positive allosteric modulators (PAMs). Our goal was to evaluate the potential for repeated administration of the mGlu5 receptor PAM, CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide) (30 mg/kg) to induce tolerance to the anti-psychotic like effect using the amphetamine-induced hyperlocomotion rat model, and to produce receptor desensitization in mGlu5 receptor-enriched brain regions. CDPPB dose dependently reduced the locomotor response to amphetamine when administered acutely, and the same effect was observed following 7-day pre-treatment regime. In addition, 7-day dosing of CDPPB did not affect mGlu5 receptor density in the striatum, nor did it change mGlu5 receptor PAM-induced phosphorylation of NMDA, GluN1 and GluN2b, receptor subunits in striatum compared to the levels measured acutely. In contrast, in the frontal cortex, repeated administration of CDPPB decreased mGlu5 receptor density and resulted in a loss of its ability to increase GluN1 and GluN2b levels. Consistent with a reduction of cortical mGlu5 receptor density and phosphorylation, CDPPB (30 mg/kg) significantly affected sleep architecture as determined by cortical EEG at day one however by the seventh day of dosing all sleep changes were absent. Together these results suggest that the development of tolerance induced by the repeated treatment with the mGlu5 receptor PAM, CDPPB, may depend not only on the system being measured (sleep architecture vs psychostimulant induced hyperactivity), but also on the brain region involved with frontal cortex being a more susceptible region to receptor desensitization and internalization than striatum.

PURPOSE: To evaluate the safety and efficacy of an embolotherapeutic technique that uses electrolytically detachable platinum coils and radio frequency (RF) energy to achieve rapid and distal occlusion of targeted vessels. METHODS: In swine, branches of the ascending cervical artery and the hepatic artery measuring 1.5 mm or less were subjected to endovascular electrocoagulation. RF energy was delivered through modified Guglielmi detachable platinum coils that were placed in the targeted arteries. Ohmic heating generated by RF caused vessel occlusion. After the vessel occlusions were confirmed angiographically, the platinum microcoils were electrolytically detached from the delivery wire and left in the vessels as implants. RESULTS: All vessels were rapidly and superselectively occluded by endovascular electrocoagulation. Following use of the appropriate methods derived from this research, we did not observe rupture of the artery, dissection of the artery, unintended occlusion, or migration of the platinum microcoil. Histologic examination of treated vessels at 6 and 12 weeks revealed obliteration of the vessel lumen by the platinum microcoil surrounded by granulation tissue. CONCLUSION: Endovascular electrocoagulation is a rapid method of achieving vessel occlusion. It may be a useful and controllable embolotherapeutic technique when expeditious occlusion of small vessels and distal superselectivity are desired.