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Background and Objectives: Dynamic craniotomy as opposed to a fixed plate craniotomy provides cranial decompression with a controlled outward bone flap movement to accommodate postoperative cerebral swelling and/or hemorrhage. The objective of this study was to evaluate if fixation of the bone flap following a trauma craniotomy with dynamic plates provides any advantage over fixed plates., Methods: A review of our clinical series of 25 consecutive adult patients undergoing dynamic craniotomy with the Khanna NuCrani reversibly expandable bone flap fixation plates for the treatment of traumatic brain injury associated with mass lesions including subdural, epidural, and cerebral hematomas was conducted., Results: Postoperative cerebral swelling was encountered in 21 of 25 patients (84%), which was compensated for with outward bone flap movement in all these patients and associated decreased midline shift. Severe brain swelling with outward bone flap movement of 8 mm or more was noted in 40% of the patients. All patients had a normal intracranial pressure after surgery. None of the patients required any reoperations for hematoma evacuation, rescue decompressive craniectomies, cranioplasty, or complications related to wound healing. The bone flap retracted after the resolution of the brain swelling, and none of the patients reported cosmetic symptoms related to bone flap or wound healing. Overall, 84% (21 of 25) of the patients achieved a good outcome., Conclusion: Craniotomy bone flap fixation with dynamic plates is an alternative to craniotomy with fixed plates. The main advantage of dynamic craniotomy over a craniotomy with fixed plates is that it allows for immediate intracranial volume expansion with reversible outward bone flap migration in patients who may develop postoperative worsening brain swelling and/or hemorrhage, with decreased need for repeat surgeries and associated complications., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Postoperative stroke is a challenging and potentially devastating complication after elective carotid endarterectomy (CEA). We previously demonstrated that transmembrane protein 166 (TMEM166) levels were directly related to neuronal damage after cerebral ischemia-reperfusion injury in rats. In this subsequent clinical study, we aimed to evaluate the prognostic value of TMEM166 in patients suffering from post-CEA strokes. Thirty-five patients undergoing uncomplicated elective CEA and 8 patients who suffered ischemic strokes after CEA were recruited. We evaluated the protein level and expression of TMEM166 in patients diagnosed with postoperative strokes and compared it to those in patients who underwent uncomplicated elective CEA. Blood samples and carotid artery plaques were collected and analyzed. High expressions of TMEM166 were detected by immunofluorescence staining and Western Blot in carotid artery plaques of all patients who underwent CEA. Furthermore, circulating TMEM166 concentrations were statistically higher in post-CEA stroke patients than in patients allocated to the control group. Mean plasma concentrations of inflammatory markers, including interleukin 6 (IL-6) and C-reactive protein (CRP), were also elevated in patients with postoperative strokes. Therefore, based on these findings, we hypothesize that elevated TMEM166 levels, accompanied by a strong inflammatory response, serve as a useful biomarker for risk assessment of postoperative stroke following CEA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Germinal matrix hemorrhage (GMH) can be a fatal condition responsible for the death of 1.7% of all neonates in the USA. The majority of GMH survivors develop long-term sequalae with debilitating comorbidities. Higher grade GMH is associated with higher mortality rates and higher prevalence of comorbidities. The pathophysiology of GMH can be broken down into two main titles: faulty hemodynamic autoregulation and structural weakness at the level of tissues and cells. Prematurity is the most significant risk factor for GMH, and it predisposes to both major pathophysiological mechanisms of the condition. Secondary brain injury is an important determinant of survival and comorbidities following GMH. Mechanisms of brain injury secondary to GMH include apoptosis, necrosis, neuroinflammation, and oxidative stress. This review will have a special focus on the mechanisms of oxidative stress following GMH, including but not limited to inflammation, mitochondrial reactive oxygen species, glutamate toxicity, and hemoglobin metabolic products. In addition, this review will explore treatment options of GMH, especially targeted therapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ischemic stroke can be a serious complication of selective carotid endarterectomy (CEA) in patients with carotid artery stenosis (CAS). The underlying risk factors and mechanisms of these postoperative strokes are not completely understood. Our previous study showed that TMEM166-induced neuronal autophagy is involved in the development of secondary brain injury following cerebral ischemia-reperfusion injury in rats. This current study aimed to investigate the role of TMEM166 in ischemic stroke following CEA. In the clinical part of this study, the quantitative analysis demonstrated circulating TMEM166, interleukin 6 (IL-6), and C-reactive protein (CRP) levels were significantly elevated in patients who suffered an ischemic stroke after CEA compared to those who did not. Furthermore, non-survivors exhibited higher levels of these proteins than survivors. In the preclinical part of this study, a middle cerebral artery occlusion (MCAO) model was implemented following CAS simulation in TMEM166 -/- mice. We found TMEM166 expression was positively correlated with the degree of ischemic brain injury. Ad5-TMEM166 transfection aggravated ischemic brain injury by inducing microglial autophagy activation and release of inflammatory cytokines. Accordingly, TMEM166 deficiency reduced brain inflammation and inhibited excessive microglial autophagy through the mammalian target of rapamycin (mTOR) pathway. These findings suggest that TMEM166 may play a key role in the development of ischemic injury after CEA and may serve as a biomarker for risk assessment of postoperative ischemic stroke.

Background: Adjacent segment disease (ASD) is a common problem after lumbar spinal fusions. Ways to reduce the rates of ASD are highly sought after to reduce the need for reoperation., Objective: To find predisposing factors of ASD after lumbar interbody fusions, especially in mismatch of pelvic incidence and lumbar lordosis (PI-LL)., Methods: We conducted a retrospective cohort study of all patients undergoing lumbar interbody fusions of less than 4 levels from June 2015 to July 2020 with at least 1 year of follow-up and in those who had obtained postoperative standing X-rays., Results: We found 243 patients who fit inclusion and exclusion criteria. Fourteen patients (5.8%) developed ASD, at a median of 24 months. Postoperative lumbar lordosis was significantly higher in the non-ASD cohort (median 46.4° ± 1.4° vs 36.9° ± 3.6°, P < .001), pelvic tilt was significantly lower in the non-ASD cohort (16.0° ± 0.66° vs 20.3° ± 2.4°, P = .002), PI-LL mismatch was significantly lower in the non-ASD cohort (5.28° ± 1.0° vs 17.1° ± 2.0°, P < .001), and age-appropriate PI-LL mismatch was less common in the non-ASD cohort (34 patients [14.8%] vs 13 [92.9%] of patients with high mismatch, P < .001). Using multivariate analysis, greater PI-LL mismatch was predictive of ASD (95% odds ratio CI = 1.393-2.458, P < .001) and age-appropriate PI-LL mismatch was predictive of ASD (95% odds ratio CI = 10.8-970.4, P < .001)., Conclusion: Higher PI-LL mismatch, both age-independent and when adjusted for age, after lumbar interbody fusion was predictive for developing ASD. In lumbar degenerative disease, correction of spinopelvic parameters should be a main goal of surgical correction., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background: Malignant lesions involving the C2 vertebral body (axis) may be challenging to treat, and not all patients with cancer are good candidates for posterior cervical or occipitocervical instrumentation., Objective: To describe a modified technique of the direct anterolateral C2 kyphoplasty using a steerable osteotome, commonly used for the treatment of thoracolumbar spinal lesions. We also report a case series of 11 patients treated with this technique at our institution., Methods: The authors performed a retrospective review of all patients who underwent a C2 kyphoplasty using the anterior midline approach from 2010 to 2020. Patient demographics, tumor characteristics, pain severity (visual analog scale), Karnofsky performance status , perioperative complications, and postoperative spinal stability were assessed., Results: The main indication for a C2 kyphoplasty was refractory neck pain. All patients tolerated the procedure well. There were no intraoperative complications. One patient developed transient dysphagia. Visual analog scale scores were 9.00 ± 1.10 preoperative and 3.73 ± 1.85 at 2 weeks and 1.67 ± 1.66 at 3 months after the procedure and continued to stay low during the remainder of the follow-up (4-60 months). The Karnofsky performance status improved from 72.73 ± 11.04 preoperatively to 82.22 ± 8.33 at 2 weeks and 86.67 ± 5.00 at 3 months after the procedure. There was no evidence of new occurrence or progression of C2 fractures., Conclusion: The anterior kyphoplasty using a steerable osteotome for tumors of the axis can result in lasting pain reduction and improved cervical stability while demonstrating a low complication rate., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Objective: Neuromuscular Scoliosis (NMS) causes severe deformity and operative correction for these patients carries high complication rates. We present a retrospective study comparing a series of consecutive patients who underwent posterior fusion via a single-surgeon (SS) approach with a consecutive series of patients treated via a dual-surgeon (DS) approach., Methods: Patients with NMS who underwent posterior fusion via a SS approach from 2019 to 2022 were analyzed and compared to a series of patients with NMS who underwent posterior fusion via a DS approach., Results: In the SS group, the average estimated blood loss (EBL) was 675 mL, average length of stay (LOS) was 6.3 days, average operative time (OT) was 6.5 hours, average packed red blood cell transfusion was 1.5 units, with a complication rate of 30%. The DS group had an average EBL of 400 mL, a LOS of 4.8 days, an OT of 4.75 hours, an average packed red blood cell transfusion of 0.8 units, with a complication rate of 20%. The DS approach was significant for a lower EBL, OT (P < 0.001), and LOS (P < 0.03)., Conclusions: This study suggests that for patients with NMS the DS approach decreases OT, EBL, complication rates, and LOS. This further supports that this approach may benefit outcomes in NMS patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Craniotomies for resection of neoplastic lesions are at increased risk for surgical site infections (SSIs) as compared to non-neoplastic pathologies. SSIs can be detrimental due to delay in pivotal adjuvant therapies., Objective: The purpose of this study was to determine the rate of SSI in primary brain tumors, to analyze risk factors, and to evaluate effectiveness of topical vancomycin in reducing SSIs., Methods: A retrospective cohort study was conducted at a National Cancer Institutedesignated Comprehensive Cancer Center. Patients with primary brain tumors (n = 799) who were subjected to craniotomy from 2004 to 2014 were included. Patient demographics, tumor characteristics, use of topical vancomycin and clinical outcomes were analyzed., Results: Topical vancomycin was associated with a significantly lower rate of SSI (0.8%) compared to standard care (5%), ( p = 0.00071; OR = 0.15; 95% CI = 0.02 - 0.5). Narcotic use ( p = 0.043; OR = 2.24; 95% CI = 0.96 - 4.81), previous brain radiation ( p = 0.043; OR = 2.08; 95% CI = 1.02 - 4.29), length of hospitalization ( p = 0.01; OR= 1.04; 95% CI = 1.01 - 1.08), and 30 day re-operation ( p = 1.58 ×10 -10; OR = 15.23; 95% CI = 7.06 - 32.71) were associated with increased risk for SSI., Conclusion: Topical vancomycin effectively reduced the rate of SSI in patients subjected to craniotomy for primary brain tumor resection. Furthermore, preoperative narcotic use, previous head/brain radiation, length of hospitalization, and 30-day reoperation were associated with increased risk of SSI., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: The aims of this study were to document the injury pattern in pediatric traumatic craniocervical dissociation (CCD) and identify features of survivors., Methods: Pediatric traumatic CCDs, diagnosed between January 2004 and July 2016, were reviewed. Survivors and nonsurvivors were compared. Categorical and continuous variables were analyzed with Fisher exact and t tests, respectively., Results: Twenty-seven children were identified; 10 died (37%). The median age was 60 months (ranges, 6-109 months [survivors], 2-98 months [nonsurvivors]). For survivors, the median follow-up was 13.4 months (range, 1-109 months). The median time to mortality was 1.5 days (range, 1-7 days). The injury modality was motor vehicle collision in 18 (67%), pedestrian struck in 8 (30%), and 1 shaken infant (3%). For nonsurvivors, CCD was equally diagnosed by plain radiograph and head/cervical spine computed tomography scan. For survivors, CCD was diagnosed by computed tomography in 7 (41%), magnetic resonance imaging in 10 (59%), and none by radiograph. Seven diagnosed by magnetic resonance imaging (41%) had nondiagnostic initial imaging but persistent neck pain. Magnetic resonance imaging was obtained and was diagnostic of CCD in all 7 (P < 0.01). Survivors required significantly less cardiopulmonary resuscitation (P < 0.01), had lower Injury Severity Scores (P < 0.01), higher Glasgow Coma Scale scores (P < 0.01), and shorter transport times (P < 0.01). Significantly more involved in motor vehicle collisions survived (P = 0.04). Nine (53%) had no disability at follow-up evaluation., Conclusions: In pediatric CCD, high-velocity mechanism, cardiac arrest, high Injury Severity Score, and low Glasgow Coma Scale score are associated with mortality. If CCD is correctly managed in the absence of cardiac arrest or traumatic brain or spinal cord injury, children may survive intact., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Thoracolumbar fractures in children are relatively uncommon and should be regarded as a separate entity from those in adults. While percutaneous pedicle fixation has emerged as an effective alternative to open fixation in adults with unstable thoracolumbar fractures, this technique is rarely applied in children. We report a 6-year-old girl with an L3 chance fracture, which was treated via short-segment percutaneous pedicle fixation. We also discussed the technical challenges and caveats of this surgical technique in young children. While potentially more challenging, percutaneous pedicle fixation is feasible in young children with thoracolumbar fractures. Specific differences between the developing and mature spine in regard to anatomical and biomechanical characteristics, including ligamentous laxity and intrinsic elasticity, should be taken into consideration. Future studies are needed to compare outcomes of minimally invasive spinal techniques to open surgery in children.

Background: Conventional surgical approaches used in the management of thoracic disc herniation (TDH) are associated with high morbidity. The development of minimally invasive and mini-open approaches has consistently improved patient outcomes., Objective: To report our experience and outcomes of patients with symptomatic TDHs who underwent discectomy and partial corpectomy using the mini-open retropleural (MORP) approach as well as provide a detailed and illustrated technical description of the approach., Methods: Retrospective chart review was performed on all patients with symptomatic TDHs who underwent a MORP approach at a tertiary academic center between 2011 and 2019. Patient demographic, clinical, and imaging data were examined (n = 33). The surgical technique is illustrated and described in detail., Results: Discectomy of the herniated thoracic discs was successfully achieved in all patients using the MORP approach. Calcified discs were present in 63.6% (n = 21) of patients. Immediate instrumentation and fusion were performed in 30.3% (n = 10) of patients, which were among the earlier cases in this series. Symptomatic pleural effusions and cerebrospinal fluid leakage occurred in 6.1% (n = 2) and 9.1% (n = 3), respectively. No patient required chest tube placement., Conclusion: The MORP approach described in this manuscript is feasible and safe in achieving discectomy in patients with symptomatic TDHs. Compared to conventional open and other minimally invasive approaches, patients undergoing the MORP approach may have better outcomes with lower complication rates., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: Every aspect of the medical field has been heavily affected by the coronavirus disease 2019 (COVID-19) pandemic, and neurosurgical services are no exception. Several departments have reported their experiences and protocols to provide insights for others impacted. The goals of this study are to report the load and variety of neurosurgical cases and clinic visits after discontinuing the COVID-19 Battle Plan at an academic tertiary care referral center to provide insights for other departments going through the same transition., Methods: The clinical data of all patients who underwent a neurosurgical intervention between May 4, 2020, and June 4, 2020 were obtained from a prospectively maintained database. Data of the control group were retrospectively collected from the medical records to compare the types of surgeries/interventions and clinic visits performed by the same neurosurgical service before the COVID-19 pandemic started., Results: One hundred sixty-one patients underwent neurosurgical interventions, and seven-hundred one patients were seen in clinic appointments, in the 4-week period following easing back from our COVID-19 "Battle Plan." Discontinuing the "Battle Plan" resulted in increases in case load to above-average practice after a week but a continued decrease in clinic appointments throughout the 4 weeks compared with average practice., Conclusions: As policy-shaping crises like pandemics abate, easing back to "typical" practice can be completed effectively by appropriately allocating resources. This can be accomplished by anticipating increases in neurosurgical volume, specifically in the functional/epilepsy and brain tumor subspecialties, as well as continued decreases in neurosurgical clinic volume, specifically in elective spine., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The growing interest in minimally invasive approaches to the thoracic and lumbar spine is mostly secondary to the high surgical morbidity and complication rates associated with conventional open approaches. The objective was to report the largest series of patients with thoracic and lumbar vertebral osteomyelitis who underwent multilevel corpectomies using the minimally invasive lateral (MIL) retropleural and retroperitoneal approaches., Methods: The surgical techniques of the MIL approaches are illustrated and described in detail. The MIL retropleural approach was performed in 9 patients, MIL retroperitoneal approach in 3 patients, and combined MIL retropleural/retroperitoneal approach in 2 patients with thoracic, lumbar and thoracolumbar vertebral osteomyelitis, respectively., Results: Multilevel corpectomies were successfully accomplished in all 14 patients using the MIL approaches (11 patients with 2-level corpectomy, 2 patients with 3-level corpectomy, and 1 patient with extension of a 3-level corpectomy to 6 levels). Correction of kyphotic deformity was achieved postoperatively in all 14 patients and remained stable with no proximal junctional kyphosis for a median of 10 months of follow-up on 10 patients; 4 patients were lost to follow-up after discharge from the hospital. Posterior instrumentation was performed in 12 patients to further support the spinal alignment., Conclusions: The MIL retropleural and retroperitoneal approaches described in this manuscript are feasible and safe in achieving multilevel corpectomies, anterior column reconstruction, and spinal deformity correction in patients with thoracic, lumbar, and thoracolumbar vertebral osteomyelitis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Neurosurgical services have been affected by the 2019 novel coronavirus disease (COVID-19) pandemic, and several departments have reported their experiences and responses to the COVID-19 crisis in an attempt to provide insights from which other impacted departments can benefit. The goals of this study were to report the load and variety of emergent/urgent neurosurgical cases after implementing the "Battle Plan" at an academic tertiary referral center during the COVID-19 pandemic and to compare these variables with previous practice at the same institution., Methods: The clinical data of all patients who underwent a neurosurgical intervention between March 23, 2020, and April 20, 2020, were obtained from a prospectively maintained database. Data of the control group were retrospectively collected from the medical records to compare the types of surgeries/interventions performed by the same neurosurgical service before the COVID-19 pandemic started., Results: Over a 4-week period during the COVID-19 pandemic, 91 patients underwent emergent, urgent, and essential neurosurgical interventions. Patient screening at teleclinics identified 11 urgent surgical cases. The implementation of the Battle Plan led to a significant decrease in the caseload, and the variation of cases by subspecialty was evident when compared with a control group comprising 214 patients., Conclusions: Delivery of optimal care and safe practice and education at an academic neurosurgical department can be well maintained with proper execution of crisis protocols. Teleclinics proved to be efficient in screening patients for urgent neurosurgical conditions, but in-person clinic visits may still be necessary for some cases in the immediate postoperative period., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In addition to being the leading cause of morbidity and mortality in premature infants, germinal matrix hemorrhage (GMH) is also the leading cause of acquired infantile hydrocephalus. The pathophysiology of posthemorrhagic hydrocephalus (PHH) development after GMH is complex and vaguely understood, although evidence suggests fibrosis and gliosis in the periventricular and subarachnoid spaces disrupts normal cerebrospinal fluid (CSF) dynamics. Theories explaining general hydrocephalus etiology have substantially evolved from the original bulk flow theory developed by Dr. Dandy over a century ago. Current clinical and experimental evidence supports a new hydrodynamic theory for hydrocephalus development involving redistribution of vascular pulsations and disruption of Starling forces in the brain microcirculation. In this review, we discuss CSF flow dynamics, history and development of theoretical hydrocephalus pathophysiology, and GMH epidemiology and etiology as it relates to PHH development. We highlight known mechanisms and propose new avenues that will further elucidate GMH pathophysiology, specifically related to hydrocephalus., (© 2019 Wiley Periodicals, Inc.)

Introduction: Implant subsidence is a potential complication of spinal interbody fusion and may negatively affect patients subjected to procedures relying on indirect decompression such as minimally invasive transpsoas lateral lumbar interbody fusion (LLIF). The porous architecture of a recently developed titanium intervertebral cage maximizes bone-to-implant contact and minimizes stress shielding in laboratory experiments; however, its subsidence rate in patients has not yet been evaluated. The goal of this current study was to evaluate implant subsidence in patients subjected to LLIF., Methods: Our institutional review board-approved single-center experience included 29 patients who underwent 30 minimally invasive LLIF from July 2017 to September 2018 utilizing the novel 3D-printed porous titanium implants. Radiographs, obtained during routine postoperative follow-up visits, were reviewed for signs of implant subsidence, defined as any appreciable compromise of the vertebral endplates., Results: Radiographic subsidence occurred in 2 cases (6.7%), involving 2 out of 59 porous titanium interbody cages (3.4%). Both cases of subsidence occurred in four-level stand-alone constructs. The patients remained asymptomatic and did not require surgical revision. Ten surgeries were stand-alone constructs, and 20 surgeries included supplemental posterior fixation., Conclusions: In our patient cohort, subsidence of the porous titanium intervertebral cage occurred in 6.7% of all cases and in 3.4% of all lumbar levels. This subsidence rate is lower compared to previously reported subsidence rates in patients subjected to LLIF using polyetheretherketone implants., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2020 by The Japanese Society for Spine Surgery and Related Research.)

The current literature indicates carotid endarterectomy (CEA) as the preferred treatment for symptomatic, moderate to severe carotid artery stenosis. However, recommendations for the management of acute tandem stenosis and complete occlusion, as well as postintervention restenosis of the carotid artery, remain controversial. Here, we review the literature evaluating these conditions and provide suggestions for clinical decision-making. Acute tandem stenosis or occlusion of the common and internal carotid arteries may be treated with angioplasty alone, reserving carotid artery stenting (CAS) or CEA for severe and complex cases. Patients who underwent CEA and developed ipsilateral restenosis may be subjected to angioplasty followed by CAS, which carries a lower risk of cranial nerve injury and subsequent restenosis of the artery. For post-CAS restenosis, current evidence recommends angioplasty and CAS for the management of moderate stenosis and CEA for severe stenosis of the carotid artery. Given the lack of level 1 evidence for the management of these conditions, the abovementioned recommendations may assist clinical decision-making; however, each case and its unique risks and benefits need to be assessed individually. Future studies evaluating and defining the risks and benefits of specific treatment strategies, such as CEA and CAS, in patients with acute tandem stenosis, occlusion, and postintervention restenosis of the carotid artery need to be conducted.

Ganglioside GM1 is a member of the ganglioside family which has been used in many countries and is thought of as a promising alternative treatment for preventing several neurological diseases, including cerebral ischemic injury. The therapeutic effects of GM1 have been proved both in neonates and in adults following ischemic brain damage; however, its clinical efficacy in patients with ischemic stroke is still uncertain. This review examines the recent knowledge of the neuroprotective properties of GM1 in ischemic stroke, collected in the past two decades. We conclude that GM1 may have potential for stroke treatment, although we need to be cautious in respect of its complications.

Targeting neuronal apoptosis after intracerebral hemorrhage (ICH) may be an important therapeutic strategy for ICH patients. Emerging evidence indicates that C1q/TNF-Related Protein 9 (CTRP9), a newly discovered adiponectin receptor agonist, exerts neuroprotection in cerebrovascular disease. The aim of this study was to investigate the anti-apoptotic role of CTRP9 after experimental ICH and to explore the underlying molecular mechanisms. ICH was induced in mice via intrastriatal injection of bacterial collagenase. Recombinant CTRP9 (rCTRP9) was administrated intranasally at 1 h after ICH. To elucidate the underlying mechanisms, adiponectin receptor1 small interfering ribonucleic acid (AdipoR1 siRNA) and selective PI3 K inhibitor LY294002 were administered prior to rCTRP9 treatment. Western blots, neurofunctional assessments, immunofluorescence staining, and Fluoro-Jade C (FJC) staining experiments were performed. Administration of rCTRP9 significantly improved both short- and long-term neurofunctional behavior after ICH. RCTRP9 treatment significantly increased the expression of AdipoR1, PI3 K, p-Akt, and Bcl-2, while at the same time was found to decrease the expression of Bax in the brain, which was reversed by inhibition of AdipoR1 and PI3 K. The neuroprotective effect of rCTRP9 after ICH was mediated by attenuation of neuronal apoptosis via the AdipoR1/PI3K/Akt signaling pathway; therefore, rCTRP9 should be further evaluated as a potential therapeutic agent for ICH patients.

Cervical spine deformity (CSD) can negatively affect the health-related quality of life (HRQOL) of patients, particularly the elderly, thus representing a socioeconomic problem of increasing importance. While surgical deformity correction has been linked to improved HRQOL, no universally accepted consensus exists for the operative management of CSD. The authors demonstrate the feasibility of CSD correction, implementing anterior and posterior cervical osteotomies combined with the placement of multiple consecutive zero-profile hyperlordotic interbody spacers in a 55-year-old male with cervical kyphosis. This technique resulted in the satisfactory restoration of the patient's cervical alignment and significantly ameliorated his presenting symptoms. The patient demonstrated maintained cervical lordosis and he remained symptom-free at the one-year follow-up. The use of multiple consecutive zero-profile cervical interbody spacers can effectively and safely be utilized for the treatment of CSD. Further studies are needed to compare this technique with other standard surgeries used for CSD correction., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose- Heme and iron are considered to be key factors responsible for secondary insults after intracerebral hemorrhage (ICH). Our previous study showed that LRP1 (low-density lipoprotein receptor-related protein-1)-Hx (hemopexin) facilitates removal of heme. The TLR7 (Toll-like receptor 7)-BTK (Bruton tyrosine kinase)-CRT (calreticulin) pathway regulates the expression of LRP1-Hx. This study is designed to clarify whether TLR7 activation facilitates heme scavenging and to establish the potential role of the BTK-CRT-LRP1-Hx signaling pathway in the pathophysiology of ICH. Methods- ICH was induced by stereotactic, intrastriatal injection of type VII collagenase. Mice received TLR7 agonist (imiquimod) via intraperitoneal injection after ICH induction. TLR7 inhibitor (ODN2088), BTK inhibitor (LFM-A13), and CRT agonist (thapsigargin) were given in different groups to further evaluate the underlying pathway. Mice were randomly divided into sham, ICH+vehicle (normal saline), ICH+Imiquimod (2.5, 5, and 10 μg/g), ICH+ODN2088, ICH+LFM-A13, ICH+thapsigargin, and ICH+ODN2088+thapsigargin. Imiquimod was administered twice daily starting at 6 hours after ICH; ODN2088 was administered by intracerebroventricular injection at 30 minutes, and LFM-A13 or thapsigargin was administered by intraperitoneal injection at 3 hours after ICH induction. Neurological scores, cognitive abilities, as well as brain edema, blood-brain barrier permeability, hemoglobin level, brain expression of TLR7/BTK/CRT/LRP1/Hx were analyzed. Results- Low dosage imiquimod significantly attenuated hematoma volume, brain edema, BBB permeability, and neurological deficits after ICH. Imiquimod also increased protein expressions of TLR7, BTK, CRT, LRP1, and Hx; ODN2088 reduced TLR7, BTK, CRT, LRP1, and Hx expressions. Conclusions- TLR7 plays an important role in heme scavenging after ICH by modulating the BTK-CRT-LRP1-Hx pathway. TLR7 may offer protective effects by promoting heme resolution and reduction of brain edema after ICH.

Most large vessel stroke patients have permanent occlusion, for which there are no current treatment options. Recent case studies have indicated delayed recanalization, that is recanalization outside of the 6-h treatment window, may lead to improved outcome. We hypothesized that delayed recanalization will restore cerebral blood flow, leading to improved function in rats. Male SD rats were subjected to pMCAO or sham surgery. Delayed recanalization was performed on either day 3, 7, or 14 after pMCAO in a subset of animals. Cerebral blood flow was monitored during suture insertion, during recanalization, and then at sacrifice. Neurological function was evaluated for 1 week after delayed recanalization and at 4 weeks post-ictus. After sacrifice, cerebral morphology was measured. Compared to no treatment, delayed recanalization restored cerebral blood flow, leading to sensorimotor recovery, improved learning and memory, reduced infarct volume, and increased neural stem/progenitor cells within the infarction. The data indicate that earlier delayed recanalization leads to better functional and histological recovery. Yet, even restoring cerebral blood flow 14 days after pMCAO allows for rats to regain sensorimotor function. This exploratory study suggests that delayed recanalization may be a viable option for treatment of permanent large vessel stroke.

We aim to determine if direct thrombin inhibition by dabigatran will improve long-term brain morphological and neurofunctional outcomes and if potential therapeutic effects are dependent upon reduced PAR-1 stimulation and consequent mTOR activation. Germinal matrix haemorrhage was induced by stereotaxically injecting 0.3 U type VII-S collagenase into the germinal matrix of P7 rat pups. Animals were divided into five groups: sham, vehicle (5% DMSO), dabigatran intraperitoneal, dabigatran intraperitoneal + TFLLR-NH 2 (PAR-1 agonist) intranasal, SCH79797 (PAR-1 antagonist) intraperitoneal, and dabigatran intranasal. Neurofunctional outcomes were determined by Morris water maze, rotarod, and foot fault evaluations at three weeks. Brain morphological outcomes were determined by histological Nissl staining at four weeks. Expression levels of p-mTOR/p-p70s6k at three days and vitronectin/fibronectin at 28 days were quantified. Intranasal and intraperitoneal dabigatran promoted long-term neurofunctional recovery, improved brain morphological outcomes, and reduced intracranial pressure at four weeks after GMH. PAR-1 stimulation tended to reverse dabigatran's effects on post-haemorrhagic hydrocephalus development. Dabigatran also reduced expression of short-term p-mTOR and long-term extracellular matrix proteins, which tended to be reversed by PAR-1 agonist co-administration. PAR-1 inhibition alone, however, did not achieve the same therapeutic effects as dabigatran administration.

Fingolimod, a sphingosine-1-phosphate receptor (S1PR) agonist, is clinically available to treat multiple sclerosis and is showing promise in treating stroke. We investigated if fingolimod provides long-term protection from experimental neonatal germinal matrix hemorrhage (GMH), aiming to support a potential mechanism of acute fingolimod-induced protection. GMH was induced in P7 rats by infusion of collagenase (0.3 U) into the right ganglionic eminence. Animals killed at 4 weeks post-GMH received low- or high-dose fingolimod (0.25 or 1.0 mg/kg) or vehicle, and underwent neurocognitive testing before histopathological evaluation. Subsequently, a cohort of animals killed at 72 h post-GMH received 1.0 mg/kg fingolimod; the specific S1PR1 agonist, SEW2871; or fingolimod co-administered with the S1PR1/3/4 inhibitor, VPC23019, or the Rac1 inhibitor, EHT1864. All drugs were injected intraperitoneally 1, 24, and 48 h post-surgery. At 72 h post-GMH, brain water content, extravasated Evans blue dye, and hemoglobin were measured as well as the expression levels of phospho-Akt, Akt, GTP-Rac1, Total-Rac1, ZO1, occludin, and claudin-3 determined. Fingolimod significantly improved long-term neurocognitive performance and ameliorated brain tissue loss. At 72 h post-GMH, fingolimod reduced brain water content and Evans blue dye extravasation as well as reversed GMH-induced loss of tight junctional proteins. S1PR1 agonism showed similar protection, whereas S1PR or Rac1 inhibition abolished the protective effect of fingolimod. Fingolimod treatment improved functional and morphological outcomes after GMH, in part, by tempering acute post-hemorrhagic blood-brain barrier disruption via the activation of the S1PR1/Akt/Rac1 pathway., (© 2017 International Society for Neurochemistry.)

Accounting for high mortality and morbidity rates, intracerebral hemorrhage (ICH) remains one of the most detrimental stroke subtypes lacking a specific therapy. Neuroinflammation contributes to ICH-induced brain injury and is associated with unfavorable outcomes. This study aimed to evaluate whether α 7 nicotinic acetylcholine receptor ( α 7nAChR) stimulation ameliorates neuroinflammation after ICH. Male CD-1 mice and Sprague-Dawley were subjected to intracerebral injection of autologous blood or bacterial collagenase. ICH animals received either α 7nAChR agonist PHA-543613 alone or combined with α 7nAChR antagonist methyllycaconitine (MLA) or Janus kinase 2 (JAK2) antagonist AG490. Neurobehavioral deficits were evaluated at 24 hours, 72 hours, and 10 weeks after ICH induction. Perihematomal expressions of JAK2, signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor- α (TNF- α ), and myeloperoxidase (MPO) were quantified via Western blot. Histologic volumetric analysis of brain tissues was conducted after 10 weeks following ICH induction. PHA-543613 improved short-term neurobehavioral (sensorimotor) deficits and increased activated perihematomal JAK2 and STAT3 expressions while decreasing TNF- α and MPO expressions after ICH. MLA reversed these treatment effects. PHA-543613 also improved long-term neurobehavioral (sensorimotor, learning, and memory) deficits and ameliorated brain atrophy after ICH. These treatment effects were reduced by AG490. α 7nAChR stimulation reduced neuroinflammation via activation of the JAK2-STAT3 pathway, thereby ameliorating the short- and long-term sequelae after ICH.

Germinal matrix hemorrhage remains the leading cause of morbidity and mortality in preterm infants in the United States with little progress made in its clinical management. Survivors are often afflicted with long-term neurological sequelae, including cerebral palsy, mental retardation, hydrocephalus, and psychiatric disorders. Blood clots disrupting normal cerebrospinal fluid circulation and absorption after germinal matrix hemorrhage are thought to be important contributors towards post-hemorrhagic hydrocephalus development. We evaluated if upregulating CD36 scavenger receptor expression in microglia and macrophages through PPARγ stimulation, which was effective in experimental adult cerebral hemorrhage models and is being evaluated clinically, will enhance hematoma resolution and ameliorate long-term brain sequelae using a neonatal rat germinal matrix hemorrhage model. PPARγ stimulation (15d-PGJ2) increased short-term PPARγ and CD36 expression levels as well as enhanced hematoma resolution, which was reversed by a PPARγ antagonist (GW9662) and CD36 siRNA. PPARγ stimulation (15d-PGJ2) also reduced long-term white matter loss and post-hemorrhagic ventricular dilation as well as improved neurofunctional outcomes, which were reversed by a PPARγ antagonist (GW9662). PPARγ-induced upregulation of CD36 in macrophages and microglia is, therefore, critical for enhancing hematoma resolution and ameliorating long-term brain sequelae., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Giant serpentine aneurysms are complex intracranial lesions, associated with a poor prognosis if left untreated. Treatment usually involves surgical trapping of the aneurysm with arterio-arterial anastomosis; however, recent endovascular management has been implemented for the management of such aneurysms., Case Description: We report the unique case of a 71-year-old woman who presented with visual deficits due to the mass effect of a giant serpentine aneurysm arising from the A1 segment of the anterior cerebral artery. Because of its location proximal to a widely patent anterior communicating artery, angiographic cure was achieved with sacrifice of the A1 segment. Clinical and radiographic follow-up demonstrated resolution of the presenting symptoms and near-complete obliteration of the aneurysm., Conclusions: Thrombosed giant serpentine aneurysms can show dramatic resolution of mass effect with endovascular treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Germinal matrix hemorrhage (GMH) is the most common cause of neurological complications of prematurity and has lasting implications. PAR-1 and PAR-4 receptors are involved with upstream signaling pathways following brain hemorrhage in adult models of stroke, of which the mammalian target of rapamycin (mTOR) is a potential downstream mediator. Therefore, we hypothesized a role for PAR-1, -4/ mTOR signaling following GMH brain injury. Postnatal day 7 Sprague-Dawley rats were subjected to GMH through stereotactic infusion of collagenase into the right ganglionic eminence. Rodents were euthanized at 72 h (short term), or 4 weeks (long term). Short-term mTOR expression was evaluated by Western blot in the context of PAR-1 (SCH-79797) and PAR-4 (P4pal10) inhibition. Pups in the long-term group were administered the selective mTOR inhibitor (rapamycin) with neurobehavioral and brain pathological examinations performed at 4 weeks. Pharmacological PAR-1, -4 antagonism normalized the increased mTOR expression following GMH. Early inhibition of mTOR by rapamycin improved long-term outcomes in rats. Mammalian-TOR signaling plays an important role in brain injury following neonatal GMH, possibly involving upstream PAR-1, -4 mechanisms.

Hemorrhagic transformation occurs in as many as 48 % of stroke patients and is a major contributor to post-insult morbidity and mortality. Experimental models of hemorrhagic transformation are utilized for understanding the mechanisms behind its development, as well as for investigating potential therapeutics for prevention and reduction of bleeding. Thoroughly studying animal models of hemorrhagic transformation is critically important for testing novel treatments. Thus far, no study has examined the progression of brain swelling and hemorrhagic transformation after transient middle cerebral artery occlusion (MCAO). Herein, we investigate the development of infarction, brain swelling, and hemorrhagic transformation following MCAO in hyperglycemic rats. Twenty-five Sprague-Dawley rats were subjected to either 1.5 h of MCAO or sham surgery 15 min after induction of hyperglycemia. Animals were sacrificed at 0.25, 1, 3, or 24 h after reperfusion for measurement of infarct volume, brain swelling, and hemoglobin volume. Within 15 min of reperfusion, the infarct volume was significantly larger than in sham animals and did not increase in size over the 24 h. However, both brain swelling and hemorrhagic transformation, which began immediately after reperfusion, increase over 24 h after reperfusion.

Germinal matrix hemorrhage (GMH) is a major cause of brain damage in prematurity and has long-lasting neurological implications. The development of brain inflammation contributes to brain injury, leading to a lifetime of neurologic deficits. PAR-1 and 4 receptors are involved with inflammatory pathways after brain hemorrhage in adult models of stroke, of which cyclooxygenase-2 (COX-2) is a potential mediator. We therefore hypothesized a role for PAR-1, 4/ COX-2 signaling following GMH. Postnatal day 7 Sprague-Dawley rats were subjected to GMH induction, which entailed stereotactic collagenase infusion into the ganglionic eminence. Animals were euthanized at two time points: 72 h (short-term) or 4 weeks (long-term). Short-term COX-2 expression was evaluated in the context of PAR-1 (SCH-79797) and PAR-4 (P4pal10) inhibition. Pups in the long-term group were administered the selective COX-2 inhibitor (NS-398); and the neurobehavioral and pathological examinations were performed 4 weeks later. Pharmacological PAR-1, 4 antagonism normalized COX-2 expression following GMH and reduced hydrocephalus. Early inhibition of COX-2 by NS-398 improved long-term neurobehavioral outcomes. COX-2 signaling plays an important role in brain injury following neonatal GMH, possibly through upstream PAR-1, 4 receptor mechanisms.

Objective: Neonatal hypoxia occurs in approximately 60% of premature births and is associated with a multitude of neurological disorders. While various treatments have been developed, translating them from bench to bedside has been limited. We previously showed G-CSF administration was neuroprotective in a neonatal hypoxia-ischemia rat pup model, leading us to hypothesize that G-CSF inactivation of GSK-3β via the PI3K/Akt pathway may attenuate neuroinflammation and stabilize the blood-brain barrier (BBB)., Methods: P10 Sprague-Dawley rat pups were subjected to unilateral carotid artery ligation followed by hypoxia for 2.5h. We assessed inflammation by measuring expression levels of IKKβ, NF-κB, TNF-α, IL-1β, IL-10, and IL-12 as well as neutrophil infiltration. BBB stabilization was evaluated by measuring Evans blue extravasation, and Western blot analysis of Claudin-3, Claudin-5, ICAM-1, and VCAM-1., Measurements and Main Results: First, the time course study showed that p-β-catenin/β-catenin, IKKβ, and NF-κB expression levels peaked at 48h post-HI. The knockdown of GSK-3β with siRNA prevented the HI-induced increase of p-β-catenin/β-catenin, IKKβ, and NF-κB expression levels 48h after HI. G-CSF treatment reduced brain water content and neuroinflammation by downregulating IKKβ, NF-κB, TNF-α, IL-1β, and IL-12 and upregulating IL-10, thereby reducing neutrophil infiltration. Additionally, G-CSF stabilizes the BBB by downregulating VCAM-1 and ICAM-1, as well as upregulating Claudins 3 and 5 in endothelial cells. G-CSFR knockdown by siRNA and Akt inhibition by Wortmannin reversed G-CSF's neuroprotective effects., Conclusions: We demonstrate G-CSF plays a pivotal role in attenuating neuroinflammation and BBB disruption following HI by inactivating GSK-3β through the PI3K/Akt pathway., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Purpose: Edema formation, inflammation and increased blood-brain barrier permeability contribute to poor outcomes after intracerebral hemorrhage (ICH). This study examined the therapeutic effect of dimethyl fumarate (DMF), a fumaric acid ester that activates nuclear factor erythroid-2 related factor 2 (Nrf2) and Nrf2 heterodimerization effector protein musculo-aponeurotic fibrosarcoma-G (MAFG) in a murine ICH model., Methods: Male CD-1 mice (n=176) were subjected to intrastriatal infusion of bacterial collagenase (n=126), autologous blood (n=18) or sham surgery (n=32). Four (4) animals not subjected to ICH (naive) were also included in the study. After ICH, animals either received vehicle, dimethyl fumarate (10 mg or 100 mg/kg) or casein kinase 2 inhibitor (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid (TBCA). Thirty-two mice also received scrambled siRNA or MAFG siRNA 24h before ICH. Brain water content and neurological function were evaluated., Results: Dimethyl fumarate reduced Evans blue dye extravasation, decreased brain water content, and improved neurological deficits at 24 and 72 h after ICH. Casein kinase 2 inhibitor TBCA and MAFG siRNA prevented the effect of dimethyl fumarate on brain edema and neurological function. After ICH, ICAM-1 levels increased and casein kinase 2 levels decreased. Dimethyl fumarate reduced ICAM-1 but enhanced casein kinase 2 levels. Again, casein kinase 2 inhibitor TBCA and MAFG siRNA abolished the effect of dimethyl fumarate on ICAM-1 and casein kinase 2. Dimethyl fumarate preserved pNrf2 and MAFG expression in the nuclear lysate after ICH and the effect of dimethyl fumarate was abolished by casein kinase 2 inhibitor TBCA and MAFG siRNA. Dimethyl fumarate reduced microglia activation in peri-hematoma areas after ICH. The protective effect of dimethyl fumarate on brain edema and neurological function was also observed in a blood injection mouse model., Conclusion: Dimethyl fumarate ameliorated inflammation, reduced blood-brain barrier permeability, and improved neurological outcomes by casein kinase 2 and Nrf2 signaling pathways after experimental ICH in mice., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Blood-brain barrier (BBB) disruption and consequent edema formation contribute to the development of early brain injury following subarachnoid hemorrhage (SAH). Various cerebrovascular insults result in increased platelet-derived growth factor receptor (PDGFR)-α stimulation, which has been linked to BBB breakdown and edema formation. This study examines whether imatinib, a PDGFR inhibitor, can preserve BBB integrity in a rat endovascular perforation SAH model. Imatinib (40 or 120 mg/kg) or a vehicle was administered intraperitoneally at 1 hr after SAH induction. BBB leakage, brain edema, and neurological deficits were evaluated. Total and phosphorylated protein expressions of PDGFR-α, c-Src, c-Jun N-terminal kinase (JNK), and c-Jun were measured, and enzymatic activities of matrix metalloproteinase (MMP)-2 and MMP-9 were determined in the injured brain. Imatinib treatment significantly ameliorated BBB leakage and edema formation 24 hr after SAH, which was paralleled by improved neurological functions. Decreased brain expressions of phosphorylated PDGFR-α, c-Src, JNK, and c-Jun as well as reduced MMP-9 activities were found in treated animals. PDGFR-α inhibition preserved BBB integrity following experimental SAH; however, the protective mechanisms remain to be elucidated. Targeting PDGFR-α signaling might be advantageous to ameliorate early brain injury following SAH., (© 2014 Wiley Periodicals, Inc.)

Granulocyte-colony stimulating factor (G-CSF), a growth factor, has known neuroprotective effects in a variety of experimental brain injury models. Herein we show that G-CSF administration attenuates neuronal apoptosis after neonatal hypoxia-ischemia (HI) via glycogen synthase kinase-3β (GSK-3β) inhibition. Ten day old Sprague-Dawley rat pups (n=157) were subjected to unilateral carotid artery ligation followed by 2.5h of hypoxia or sham surgery. HI animals received control siRNA, GSK-3β siRNA (4 μL/pup), G-CSF (50 μg/kg), G-CSF combined with 0.1 or 0.4 nM G-CSF receptor (G-CSFR) siRNA, phosphatidylinositol 3-kinase (PI3K) inhibitor Wortmannin (86 ng/pup), or DMSO (vehicle for Wortmannin). Pups were euthanized 48 h post-HI to quantify brain infarct volume. G-CSFR, activated Akt (p-Akt), activated GSK-3β (p-GSK-3β), Cleaved Caspase-3 (CC3), Bcl-2, and Bax were quantified using Western blot analysis and the localizations of each was visualized via immunofluorescence staining. Neuronal cell death was determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Our results showed p-GSK-3β increased after HI until its peak at 48 h post-ictus, and both GSK-3β siRNA and G-CSF administration reduced p-GSK-3β expression, as well as infarct volume. p-GSK-3β and CC3 were generally co-localized in neurons. Furthermore, G-CSF increased p-Akt expression and the Bcl-2/Bax ratio and also decreased p-GSK-3β and CC3 expression levels in the ipsilateral hemisphere, which were all reversed by G-CSFR siRNA, Wortmannin, and GSK-3β siRNA. In conclusion, G-CSF attenuated caspase activation and reduced brain injury by inhibiting GSK-3β activity after experimental HI in rat pups. This neuroprotective effect was abolished by both G-CSFR siRNA and Wortmannin., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Autophagy involves degradation of dysfunctional cellular components through the actions of lysosomes. Apoptosis is the process of programmed cell death involving a series of characteristic cell changes. Autophagy and apoptosis, as self-destructive processes, play an important role in the pathogenesis of neurological diseases; and a crosstalk between "self-eating" (autophagy) and "self-killing" (apoptosis) plays an important role in pathological cellular adaptation. Expert knowledge of autophagy and apoptosis has increased in recent years, particularly in regards to cellular and molecular mechanisms. The crosstalk between autophagy and apoptosis was partially uncovered and several key molecules, including Bcl-2 family members, Beclin 1, and p53 were identified. However, the precise mechanisms of such a crosstalk remain to be elucidated. This current review article aims to summarize key mediators of the autophagy-apoptosis crosstalk in pathological conditions, and to highlight recent advances in the field, as well as to discuss further investigations and therapeutic potentials of manipulating those mechanisms in central nervous system diseases.

Neonatal brain hemorrhage (NBH) of prematurity is an unfortunate consequence of preterm birth. Complications result in shunt dependence and long-term structural changes such as posthemorrhagic hydrocephalus, periventricular leukomalacia, gliosis, and neurological dysfunction. Several animal models are available to study this condition, and many basic mechanisms, etiological factors, and outcome consequences, are becoming understood. NBH is an important clinical condition, of which treatment may potentially circumvent shunt complication, and improve functional recovery (cerebral palsy, and cognitive impairments). This review highlights key pathophysiological findings of the neonatal vascular-neural network in the context of molecular mechanisms targeting the posthemorrhagic hydrocephalus affecting this vulnerable infant population.

Background and Purpose: This study investigated if acute and delayed deferoxamine treatment attenuates long-term sequelae after germinal matrix hemorrhage (GMH)., Methods: Bacterial collagenase (0.3 U) was infused intraparenchymally into the right hemispheric ganglionic eminence in P7 rat pups to induce GMH. GMH animals received either deferoxamine or vehicle twice a day for 7 consecutive days. Deferoxamine administration was initiated at either 1 hour or 72 hours post-GMH. Long-term neurocognitive deficits and motor coordination were assessed using Morris water maze, rotarod, and foot fault tests between day 21 to 28 post-GMH. At 28 days post-GMH, brain morphology was assessed and extracellular matrix protein (fibronectin and vitronectin) expression was determined., Results: Acute and delayed deferoxamine treatment improved long-term motor and cognitive function at 21 to 28 days post-GMH. Attenuated neurofunction was paralleled with improved overall brain morphology at 28 days post-GMH, reducing white matter loss, basal ganglia loss, posthemorrhagic ventricular dilation, and cortical loss. GMH resulted in significantly increased expression of fibronectin and vitronectin, which was reversed by acute and delayed deferoxamine treatment., Conclusions: Acute and delayed deferoxamine administration ameliorated long-term sequelae after GMH., (© 2014 American Heart Association, Inc.)

Early brain injury (EBI), following subarachnoid hemorrhage (SAH), comprises blood-brain barrier (BBB) disruption and consequent edema formation. Peripheral leukocytes can infiltrate the injured brain, thereby aggravating BBB leakage and neuroinflammation. Thus, anti-inflammatory pharmacotherapies may ameliorate EBI and provide neuroprotection after SAH. Cannabinoid type 2 receptor (CB2R) agonism has been shown to reduce neuroinflammation; however, the precise protective mechanisms remain to be elucidated. This study aimed to evaluate whether the selective CB2R agonist, JWH133 can ameliorate EBI by reducing brain-infiltrated leukocytes after SAH. Adult male Sprague-Dawley rats were randomly assigned to the following groups: sham-operated, SAH with vehicle, SAH with JWH133 (1.0mg/kg), or SAH with a co-administration of JWH133 and selective CB2R antagonist SR144528 (3.0mg/kg). SAH was induced by endovascular perforation, and JWH133 was administered 1h after surgery. Neurological deficits, brain water content, Evans blue dye extravasation, and Western blot assays were evaluated at 24h after surgery. JWH133 improved neurological scores and reduced brain water content; however, SR144528 reversed these treatment effects. JWH133 reduced Evans blue dye extravasation after SAH. Furthermore, JWH133 treatment significantly increased TGF-β1 expression and prevented an SAH-induced increase in E-selectin and myeloperoxidase. Lastly, SAH resulted in a decreased expression of the tight junction protein zonula occludens-1 (ZO-1); however, JWH133 treatment increased the ZO-1 expression. We suggest that CB2R stimulation attenuates neurological outcome and brain edema, by suppressing leukocyte infiltration into the brain through TGF-β1 up-regulation and E-selectin reduction, resulting in protection of the BBB after SAH., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Formation of brain edema after intracerebral hemorrhage (ICH) is highly associated with its poor outcome. However, the relationship between cerebral edema and behavioral deficits has not been thoroughly examined in the preclinical setting. Hence, this study aimed to evaluate the ability of common sensorimotor tests to predict the extent of brain edema in two mouse models of ICH. One hundred male CD-1 mice were subjected to sham surgery or ICH induction via intrastriatal injection of either autologous blood (30 μL) or bacterial collagenase (0.0375U or 0.075U). At 24 and 72 h after surgery, animals underwent a battery of behavioral tests, including the modified Garcia neuroscore (Neuroscore), corner turn test (CTT), forelimb placing test (FPT), wire hang task (WHT) and beam walking (BW). Brain edema was evaluated via the wet weight/dry weight method. Intrastriatal injection of autologous blood or bacterial collagenase resulted in a significant increase in brain water content and associated sensorimotor deficits (p<0.05). A significant correlation between brain edema and sensorimotor deficits was observed for all behavioral tests except for WHT and BW. Based on these findings, we recommend implementing the Neuroscore, CTT and/or FPT in preclinical studies of unilateral ICH in mice., (Copyright © 2014 Elsevier B.V. All rights reserved.)