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1.  Neuroprotective Properties of Citicoline: Facts, Doubts and Unresolved Issues 
CNS Drugs  2014;28:185-193.
Citicoline is the generic name of the pharmaceutical substance that chemically is cytidine-5′-diphosphocholine (CDP-choline), which is identical to the natural intracellular precursor of phospholipid phosphatidylcholine. Following injection or ingestion, citicoline is believed to undergo quick hydrolysis and dephosphorylation to yield cytidine and choline, which then enter the brain separately and are used to resynthesize CDP-choline inside brain cells. Neuroprotective activity of citicoline has been repeatedly shown in preclinical models of brain ischaemia and trauma, but two recent, large, pivotal clinical trials have revealed no benefits in ischaemic stroke and traumatic brain injury. However, the substance seems to be beneficial in some slowly advancing neurodegenerative disorders such as glaucoma and mild vascular cognitive impairment. This paper critically discusses issues related to the clinical pharmacology of citicoline, including its pharmacokinetics/biotransformation and pharmacodynamics/mode of action. It is concluded that at present, there is no adequate description of the mechanism(s) of the pharmacological actions of this substance. The possibility should be considered and tested that, in spite of apparently fast catabolism, the intact citicoline molecule or the phosphorylated intermediate products of its hydrolysis, cytidine monophosphate and phosphocholine, are pharmacologically active.
PMCID: PMC3933742  PMID: 24504829
Journal of neurosurgery  2011;115(1):116-123.
Intracerebral hemorrhage (ICH) is associated with significant patient morbidity and mortality. Acute hematoma enlargement is an important predictor of neurological injury and poor clinical prognosis; however, neurosurgical clot evacuation may not be feasible in all patients and treatment options remain largely supportive. Thus, novel therapeutic approaches to promote hematoma resolution are needed. In the present study, we investigated whether the curry spice, curcumin, limited neurovascular injury following ICH in mice.
ICH was induced in adult male CD-1 mice by the intracerebral administration of collagenase or autologous blood. Clinically-relevant doses of curcumin (75–300 mg/kg) were administered up to 6 hours after ICH and hematoma volume, inflammatory gene expression, blood-brain barrier permeability, and brain edema were assessed over the first 72 hours. Neurological assessments were performed to correlate neurovascular protection with functional outcomes.
Curcumin increased hematoma resolution at 72 hours post-ICH. This effect was associated with a significant reduction in the expression of the pro-inflammatory mediators, tumor necrosis factor-α, interleukin-6, and interleukin-1β. Curcumin also reduced disruption of the blood-brain barrier and attenuated the formation of vasogenic edema following ICH. Consistent with the reduction in neuroinflammation and neurovascular injury, curcumin significantly improved neurological outcome scores after ICH.
Curcumin promoted hematoma resolution and limited neurological injury following ICH. These data may indicate clinical utility for curcumin as an adjunct therapy to reduce brain injury and improve patient outcome.
PMCID: PMC3153730  PMID: 21417704
Hemorrhagic stroke; vasogenic edema; blood-brain barrier; hematoma
3.  Necrostatin-1 Reduces Neurovascular Injury after Intracerebral Hemorrhage 
Intracerebral hemorrhage (ICH) is the most common form of hemorrhagic stroke, accounting for 15% of all strokes. ICH has the highest acute mortality and the worst long-term prognosis of all stroke subtypes. Unfortunately, the dearth of clinically effective treatment options makes ICH the least treatable form of stroke, emphasizing the need for novel therapeutic targets. Recent work by our laboratory identified a novel role for the necroptosis inhibitor, necrostatin-1, in limiting neurovascular injury in tissue culture models of hemorrhagic injury. In the present study, we tested the hypothesis that necrostatin-1 reduces neurovascular injury after collagenase-induced ICH in mice. Necrostatin-1 significantly reduced hematoma volume by 54% at 72 h after-ICH, as compared to either sham-injured mice or mice administered an inactive, structural analogue of necrostatin-1. Necrostatin-1 also limited cell death by 48%, reduced blood-brain barrier opening by 51%, attenuated edema development to sham levels, and improved neurobehavioral outcomes after ICH. These data suggest a potential clinical utility for necrostatin-1 and/or novel necroptosis inhibitors as an adjunct therapy to reduce neurological injury and improve patient outcomes after ICH.
PMCID: PMC3963111
4.  Preclinical and clinical research on inflammation after intracerebral hemorrhage 
Progress in neurobiology  2010;92(4):463-477.
Intracerebral hemorrhage (ICH) is one of the most lethal stroke subtypes. Despite the high morbidity and mortality associated with ICH, its pathophysiology has not been investigated as well as that of ischemic stroke. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. For example, in preclinical ICH models, microglial activation has been shown to occur within 1 h, much earlier than neutrophil infiltration. Recent advances in our understanding of neuroinflammatory pathways have revealed several new molecular targets, and related therapeutic strategies have been tested in preclinical ICH models. This review summarizes recent progress made in preclinical models of ICH, surveys preclinical and clinical studies of inflammatory cells (leukocytes, macrophages, microglia, and astrocytes) and inflammatory mediators (matrix metalloproteinases, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron), and highlights the emerging areas of therapeutic promise.
PMCID: PMC2991407  PMID: 20713126
Heme oxygenase; Hemorrhagic stroke; Leukocytes; Matrix Metalloproteinase; Microglia; NF-E2-related factor 2; Iron
5.  CDP-choline liposomes provide significant reduction in infarction over free CDP-choline in stroke 
Brain research  2005;1058(1-2):193-197.
Cytidine-5′-diphosphocholine (CDP-choline, Citicoline, Somazina) is in clinical use (intravenous administration) for stroke treatment in Europe and Japan, while USA phase III stroke clinical trials (oral administration) were disappointing. Others showed that CDP-choline liposomes significantly increased brain uptake over the free drug in cerebral ischemia models. Liposomes were formulated as DPPC, DPPS, cholesterol, GM1 ganglioside; 7/4/7/1.57 molar ratio or 35.8/20.4/35.8/8.0 mol%. GM1 ganglioside confers long-circulating properties to the liposomes by suppressing phagocytosis. CDP-choline liposomes deliver the agent intact to the brain, circumventing the rate-limiting, cytidine triphosphate:phosphocholine cytidylyltransferase in phosphatidylcholine synthesis. Our data show that CDP-choline liposomes significantly ( P < 0.01) decreased cerebral infarction (by 62%) compared to the equivalent dose of free CDP-choline (by 26%) after 1 h focal cerebral ischemia and 24 h reperfusion in spontaneously hypertensive rats. Beneficial effects of CDP-choline liposomes in stroke may derive from a synergistic effect between the phospholipid components of the liposomes and the encapsulated CDP-choline.
PMCID: PMC1939829  PMID: 16153613
Blood–brain barrier; cytidine triphosphate:phosphocholine cytidylyltransferase; Focal cerebral ischemia; CNS injury; Cytidine-5′-diphosphocholine; Citicoline; Ischemic injury volume; Somazina
6.  Molecular pathophysiology of cerebral hemorrhage: Secondary brain injury 
Intracerebral hemorrhage (ICH) is an often fatal type of stroke which kills about 30,000 people annually in the USA. If the patient survives the ictus, the resulting hematoma within brain parenchyma triggers a series of adverse events causing secondary insults and severe neurological deficits. This article discusses selected aspects of secondary brain injury after ICH and outlines key mechanisms associated with hematoma toxicity, oxidative stress, and inflammation. Finally, this review discusses the relevance of hematoma resolution processes as a target for ICH therapy, and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with ICH injury.
PMCID: PMC3123894  PMID: 21527759
Intracerebral hemorrhage; hematoma toxicity; oxidative stress; hematoma clearance; Nrf2; PPARγ; NF-κB
7.  Human Neural Stem Cells Over-Expressing VEGF Provide Neuroprotection, Angiogenesis and Functional Recovery in Mouse Stroke Model 
PLoS ONE  2007;2(1):e156.
Intracerebral hemorrhage (ICH) is a lethal stroke type. As mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs) selectively migrate to the brain and induce behavioral recovery in rat ICH model, and that combined administration of NSCs and vascular endothelial growth factor (VEGF) results in improved structural and functional outcome from cerebral ischemia.
Methods and Findings
We postulated that human NSCs overexpressing VEGF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs, increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by unilateral injection of bacterial collagenase into striatum. HB1.F3.VEGF human NSC line produced an amount of VEGF four times higher than parental F3 cell line in vitro, and induced behavioral improvement and 2–3 fold increase in cell survival at two weeks and eight weeks post-transplantation.
Brain transplantation of F3 human NSCs over-expressing VEGF near ICH lesion sites provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results suggest a possible application of the human neural stem cell line, which is genetically modified to over-express VEGF, as a therapeutic agent for ICH-stroke.
PMCID: PMC1764718  PMID: 17225860
8.  Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy 
Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages, microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. Importantly, there is increasing recognition that this dysfunction plays a critical aging secondary role in many neurodegenerative diseases, including Alzheimer’s disease (AD). Atherosclerosis, hypertension, and CAA are the most common causes of blood brain barrier (BBB) lesions. The accumulation of amyloid beta (Aβ) in the cerebrovascular system is a significant risk factor for intracerebral hemorrhage (ICH), and has been linked to endothelial transport failure and blockage of perivascular drainage. Moreover, recent anti-Aβ immunotherapy clinical trials demonstrated efficient clearance of parenchymal amyloid deposits, but have been plagued by CAA-associated adverse events. While management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA. Thus, there is a critical need for new strategies that improve BBB function and limit the development of beta-amyloidosis in the cerebral vasculature.
PMCID: PMC2958685  PMID: 20955427
Alzheimer disease; cerebral amyloid angiopathy; blood brain barrier; immunotherapy; hypertension
9.  Factors associated with in-hospital mortality following intracerebral hemorrhage: a three-year study in Tehran, Iran 
BMC Neurology  2004;4:9.
Primary intracerebral hemorrhage (ICH) is one of the common vascular insults with a relatively high rate of mortality. The aim of the current study was to determine the mortality rate and to evaluate the influence of various factors on the mortality of patients with intracerebral hemorrhage (ICH). Demographic characteristics along with clinical features and neuroimaging information on 122 patients with primary ICH admitted to Sina Hospital between 1999–2002 were assessed by multivariate analysis.
Of 122 patients diagnosed with intracerebral hemorrhage, 70 were men and 52 were women. Sixtynine percent of subjects were between 60 to 80 years of age. A history of hypertension was the primary cause in 67.2% of participants and it was found more frequent compared to other cardiovascular risk factors such as a history of ischemic heart disease (17.2%), diabetes mellitus (18%) and cigarette smoking (13.1%).
The overall mortality rate among ICH patients admitted to the hospital was 46.7%. About one third of the deaths occurred within the first two days after brain injury. Factor independently associated with in-hospital mortality were Glasgow Coma Scale (GCS) score (≤ 8), diabetes mellitus disease, volume of hematoma and and intraventricular hematoma.
Higher rate of mortality were observed during the first two weeks of hospitalization following ICH. Neuroimaging features along with GCS score can help the clinicians in developing their prognosis.
PMCID: PMC449712  PMID: 15193159
Intracerebral hemorrhage; stroke; GCS; outcome
10.  European Research Priorities for Intracerebral Haemorrhage 
Over 2 million people are affected by intracerebral haemorrhage (ICH) worldwide every year, one third of them dying within 1 month, and many survivors being left with permanent disability. Unlike most other stroke types, the incidence, morbidity and mortality of ICH have not declined over time. No standardised diagnostic workup for the detection of the various underlying causes of ICH currently exists, and the evidence for medical or surgical therapeutic interventions remains limited. A dedicated European research programme for ICH is needed to identify ways to reduce the burden of ICH-related death and disability. The European Research Network on Intracerebral Haemorrhage EURONICH is a multidisciplinary academic research collaboration that has been established to define current research priorities and to conduct large clinical studies on all aspects of ICH.
PMCID: PMC3712813  PMID: 21986448
Intracerebral haemorrhage; Oedema; Stroke; Mortality; Disability; Outcome; Pathophysiology; Epidemiology; Imaging
11.  Update in Intracerebral Hemorrhage 
The Neurohospitalist  2011;1(3):148-159.
Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is defined as bleeding within the brain parenchyma. Intracranial hemorrhage includes bleeding within the cranial vault and encompasses ICH, subdural hematoma, epidural bleeds, and subarachnoid hemorrhage (SAH). This review will focus only on ICH. This stroke subtype accounts for about 10% of all strokes. The hematoma locations are deep or ganglionic, lobar, cerebellar, and brain stem in descending order of frequency. Intracerebral hemorrhage occurs twice as common as SAH and is equally as deadly. Risk factors for ICH include hypertension, cerebral amyloid angiopathy, advanced age, antithrombotic therapy and history of cerebrovascular disease. The clinical presentation is “stroke like” with sudden onset of focal neurological deficits. Noncontrast head computerized tomography (CT) scan is the standard diagnostic tool. However, newer neuroimaging techniques have improved the diagnostic yield in terms of underlying pathophysiology and may aid in prognosis. Intracerebral hemorrhage is a neurological emergency. Medical care begins with stabilization of airway, breathing function, and circulation (ABCs), followed by specific measures aimed to decrease secondary neurological damage and to prevent both medical and neurological complications. Reversal of coagulopathy when present is of the essence. Blood pressure management can be key and continues as an area of debate and ongoing research. Surgical evacuation of ICH is of unproven benefit though a subset of well-selected patients may have improved outcomes. Ventriculostomy and intracranial pressure (ICP) monitoring are interventions also used in this patient population. To date, hemostatic medications and neuroprotectants have failed to result in clinical improvement. A multidisciplinary approach is recommended, with participation of vascular neurology, vascular neurosurgery, critical care, and rehabilitation medicine as the main players.
PMCID: PMC3726132  PMID: 23983850
intracerebral hemorrhage; diagnosis; treatment; prognosis; surgery
12.  Challenges and controversies in the medical management of primary and antithrombotic-related intracerebral hemorrhage 
Intracerebral hemorrhage (ICH) represents 10–15% of all cerebrovascular events, and is associated with substantial morbidity and mortality. In contrast to ischemic cerebrovascular disease in which acute therapies have proven beneficial, ICH remains a more elusive condition to treat, and no surgical procedure has proven to be beneficial. Aspects pertinent to medical ICH management include cessation or minimization of hematoma enlargement, prevention of intraventricular extension, and treatment of edema and mass effect. Therapies focusing on these aspects include prothrombotic (hemostatic) agents, antihypertensive strategies, and antiedema therapies. Therapies directed towards the reversal of antithrombosis caused by antiplatelet and anticoagulant agents are frequently based on limited data, allowing for diverse opinions and practice styles. Several newer anticoagulants that act by direct thrombin or factor Xa inhibition have no natural antidote, and are being increasingly used for various prophylactic and therapeutic indications. As such, these new anticoagulants will inevitably pose major challenges in the treatment of patients with ICH. Ongoing issues in the management of patients with ICH include the need for effective treatments that not only limit hematoma expansion but also result in improved clinical outcomes, the identification of patients at greatest risk for continued hemorrhage who may most benefit from treatment, and the initiation of therapies during the hyperacute period of most active hemorrhage. Defining hematoma volume increases at various anatomical locations that translate into clinically meaningful outcomes will also aid in directing future trials for this disease. The focus of this review is to underline and discuss the various controversies and challenges involved in the medical management of patients with primary and antithrombotic-related ICH.
PMCID: PMC3251899  PMID: 22276075
antithrombotic; challenges; controversies; hematoma expansion; intracerebral hemorrhage; medical management; primary; review
13.  Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage 
Experimental neurology  2012;241:45-55.
T-lymphocytes promote cerebral inflammation, thus aggravating neuronal injury after stroke. Fingolimod, a sphingosine 1-phosphate receptor analog, prevents the egress of lymphocytes from primary and secondary lymphoid organs. Based on these findings, we hypothesized fingolimod treatment would reduce the number of T-lymphocytes migrating into the brain, thereby ameliorating cerebral inflammation following experimental intracerebral hemorrhage (ICH). We investigated the effects of fingolimod in two well-established murine models of ICH, implementing intrastriatal infusions of either bacterial collagenase (cICH) or autologous blood (bICH). Furthermore, we tested the long term neurological improvements by Fingolimod in a collagenase-induced rat model of ICH. Fingolimod, in contrast to vehicle administration alone, improved neurological functions and reduced brain edema at 24 and 72 hours following experimental ICH in CD-1 mice (n=103; p<0.05). Significantly fewer lymphocytes were found in blood and brain samples of treated animals when compared to the vehicle group (p<0.05). Moreover, fingolimod treatment significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (INF-γ), and interleukin-17 (IL-17) in the mouse brain at 72 hours post-cICH (p<0.05 compared to vehicle). Long-term neurocognitive performance and histopathological analysis were evaluated in Sprague-Dawley rats between 8 and 10 weeks post-cICH (n=28). Treated rats showed reduced spatial and motor learning deficits, along with significantly reduced brain atrophy and neuronal cell loss within the basal ganglia (p<0.05 compared to vehicle). We conclude that fingolimod treatment ameliorated cerebral inflammation, at least to some extent, by reducing the availability and subsequent brain infiltration of T-lymphocytes, which improved the short and long-term sequelae after experimental ICH in rodents.
PMCID: PMC3570752  PMID: 23261767
Intracerebral hemorrhage; Fingolimod; Lymphocyte; Inflammation; Neuroprotection; Brain Edema; Behavior
14.  Thrombolytic Evacuation of Intracerebral and Intraventricular Hemorrhage 
Current cardiology reports  2012;14(6):754-760.
Intracranial hemorrhage (ICH) accounts for 10–15% of all strokes, however it causes 30–50% of stroke related mortality, disability and cost. The prevalence increases with age with only 2 cases/100,000/year for age less than 40 years to almost 350 cases/100,000/year for age more than 80 years. Several trials of open surgical evacuation of ICH have failed to show clear benefit over medical management. But, some small trials of minimal invasive hematoma evacuation in combination with thrombolytics have shown encouraging results. Based on these findings larger clinical trials are being undertaken to optimize and define therapeutic benefit of minimally invasive surgery in combination with thrombolytic clearance of hematoma. In this article we will review some of the background of minimally invasive surgery and the use of thrombolytics in the setting of ICH and intraventricular hemorrhage (IVH) and will highlight the early findings of MISTIE and CLEAR trials for these two entities respectively.
PMCID: PMC3491164  PMID: 22945285
Intracranial hemorrhage; intracerebral hemorrhage; Intraventricular hemorrhage; Minimally invasive surgery; thrombolytics
15.  The Citicoline Brain Injury Treatment (COBRIT) Trial: Design and Methods 
Journal of Neurotrauma  2009;26(12):2207-2216.
Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. Despite numerous prior clinical trials no standard pharmacotherapy for the treatment of TBI has been established. Citicoline, a naturally occurring endogenous compound, offers the potential of neuroprotection, neurorecovery, and neurofacilitation to enhance recovery after TBI. Citicoline has a favorable side-effect profile in humans and several meta-analyses suggest a benefit of citicoline treatment in stroke and dementia. COBRIT is a randomized, double-blind, placebo-controlled, multi-center trial of the effects of 90 days of citicoline on functional outcome in patients with complicated mild, moderate, and severe TBI. In all, 1292 patients will be recruited over an estimated 32 months from eight clinical sites with random assignment to citicoline (1000 mg twice a day) or placebo (twice a day), administered enterally or orally. Functional outcomes are assessed at 30, 90, and 180 days after the day of randomization. The primary outcome consists of a set of measures that will be analyzed as a composite measure using a global test procedure at 90 days. The measures comprise the following core battery: the California Verbal Learning Test II; the Controlled Oral Word Association Test; Digit Span; Extended Glasgow Outcome Scale; the Processing Speed Index; Stroop Test part 1 and Stroop Test part 2; and Trail Making Test parts A and B. Secondary outcomes include survival, toxicity, and rate of recovery.
PMCID: PMC2824223  PMID: 19803786
citicoline; clinical trial; COBRIT; therapy; traumatic brain injury
16.  Experimental intracerebral hemorrhage: avoiding pitfalls in translational research 
Intracerebral hemorrhage (ICH) has the highest mortality of all stroke subtypes, yet treatments are mainly limited to supportive management, and surgery remains controversial. Despite significant advances in our understanding of ICH pathophysiology, we still lack preclinical models that accurately replicate the underlying mechanisms of injury. Current experimental ICH models (including autologous blood and collagenase injection) simulate different aspects of ICH-mediated injury but lack some features of the clinical condition. Newly developed models, notably hypertension- and oral anticoagulant therapy-associated ICH models, offer added benefits but further study is needed to fully validate them. Here, we describe and discuss current approaches to experimental ICH, with suggestions for changes in how this condition is studied in the laboratory. Although advances in imaging over the past few decades have allowed greater insight into clinical ICH, there remains an important role for experimental models in furthering our understanding of the basic pathophysiologic processes underlying ICH, provided limitations of animal models are borne in mind. Owing to differences in existing models and the failed translation of benefits in experimental ICH to clinical practice, putative neuroprotectants should be trialed in multiple models using both histological and functional outcomes until a more accurate model of ICH is developed.
PMCID: PMC3210340  PMID: 21863040
animal models; experimental; inflammation; intracerebral hemorrhage; translational medicine
17.  Tumor necrosis factor alpha antagonism improves neurological recovery in murine intracerebral hemorrhage 
Intracerebral hemorrhage (ICH) is a devastating stroke subtype characterized by a prominent neuroinflammatory response. Antagonism of pro-inflammatory cytokines by specific antibodies represents a compelling therapeutic strategy to improve neurological outcome in patients after ICH. To test this hypothesis, the tumor necrosis factor alpha (TNF-α) antibody CNTO5048 was administered to mice after ICH induction, and histological and functional endpoints were assessed.
Using 10 to 12-week-old C57BL/6J male mice, ICH was induced by collagenase injection into the left basal ganglia. Brain TNF-α concentration, microglia activation/macrophage recruitment, hematoma volume, cerebral edema, and rotorod latency were assessed in mice treated with the TNF-α antibody, CNTO5048, or vehicle.
After ICH induction, mice treated with CNTO5048 demonstrated reduction in microglial activation/macrophage recruitment compared to vehicle-treated animals, as assessed by unbiased stereology (P = 0.049). This reduction in F4/80-positive cells was associated with a reduction in cleaved caspase-3 (P = 0.046) and cerebral edema (P = 0.026) despite similar hematoma volumes, when compared to mice treated with vehicle control. Treatment with CNTO5048 after ICH induction was associated with a reduction in functional deficit when compared to mice treated with vehicle control, as assessed by rotorod latencies (P = 0.024).
Post-injury treatment with the TNF-α antibody CNTO5048 results in less neuroinflammation and improved functional outcomes in a murine model of ICH.
PMCID: PMC3765285  PMID: 23962089
Intracerebral hemorrhage; Microglia; Tumor necrosis factor alpha antagonism; Murine model; Cytokine; Remicade
18.  Astrocyte-Specific Expression of Survivin after Intracerebral Hemorrhage in Mice: A Possible Role in Reactive Gliosis? 
Journal of Neurotrauma  2012;29(18):2798-2804.
Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, accounts for up to 15% of all strokes. Despite maximal surgical intervention and supportive care, ICH is associated with significant morbidity and mortality, in part due to a lack of viable treatment options. Astrogliosis, a key feature of secondary injury that is characterized by glial proliferation, is a poorly-defined process that may produce both beneficial and detrimental outcomes after brain injury. Using a pre-clinical murine model of collagenase-induced ICH, we demonstrate a delayed upregulation of survivin, a key molecule involved in tumor cell proliferation and survival, by 72 h post-ICH. Notably, this increase in survivin expression was prominent in GFAP-positive astrocytes, but absent in neurons. Survivin was not expressed at detectable levels in the striatum of sham-operated mice. The expression of survivin after ICH was temporally and spatially associated with the expression of proliferating cell nuclear antigen (PCNA), an established marker of cellular proliferation. Moreover, the survivin expression was co-localized in proliferating astrocytes as evidenced by triple-label immunohistochemistry. Finally, shRNA-mediated silencing of survivin expression attenuated PCNA expression and reduced cellular proliferation in human glial cells. Together, these data suggest a potentially novel role for survivin in functionally promoting astrocytic proliferation after ICH.
PMCID: PMC3521135  PMID: 22862734
astrogliosis; Inhibitor of Apoptosis protein family; proliferation; repair; stroke
19.  Advances in Neuroprotective Strategies: Potential Therapies for Intracerebral Hemorrhage 
Intracerebral hemorrhage (ICH) is associated with higher mortality and morbidity than any other form of stroke. However, there currently are no treatments proven to improve outcomes after ICH, and therefore, new effective therapies are urgently needed. Growing insight into ICH pathophysiology has led to the development of neuroprotective strategies that aim to improve the outcome through reduction of secondary pathologic processes. Many neuroprotectants target molecules or pathways involved in hematoma degradation, inflammation or apoptosis, and have demonstrated potential clinical benefits in experimental settings. We extensively reviewed the current understanding of ICH pathophysiology as well as promising experimental neuroprotective agents with particular focus on their mechanisms of action. Continued advances in ICH knowledge, increased understanding of neuroprotective mechanisms, and improvement in the ability to modulate molecular and pathologic events with multitargeting agents will lead to successful clinical trials and bench-to-bedside translation of neuroprotective strategies.
PMCID: PMC3721946  PMID: 21178344
Intracerebral hemorrhage; Pathophysiology; Neuroprotection; Secondary cerebral injury, mechanism
20.  Experimental Model of Warfarin-Associated Intracerebral Hemorrhage 
Background and Purpose
Future demographic changes predict an increase in the number of patients with atrial fibrillation. As long-term anticoagulation for the prevention of ischemic strokes becomes more prevalent, the burden of warfarin-associated intracerebral hemorrhage (W-ICH) is likely to grow. However, little is known about the clinical aspects and pathophysiologic mechanisms of W-ICH. This study describes the development of a mouse model of W-ICH in which hematoma growth and outcomes can be correlated with anticoagulation parameters.
CD-1 mice were treated with warfarin (2 mg/kg per 24 hours) added to drinking water. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum. Hemorrhagic blood volume was quantified by means of a photometric hemoglobin assay 2 and 24 hours after hemorrhage induction. Neurologic outcomes were assessed on a 5-point scale.
The international normalized ratio in nonanticoagulated mice was 0.8±0.1. After 24 (W-24) and 30 (W-30) hours of warfarin pretreatment, international normalized ratio values increased to 3.5±0.9 and 7.2±3.4, respectively. Compared with nonanticoagulated mice, mean hemorrhagic blood volume determined 24 hours after hemorrhage induction was found to be 2.5-fold larger in W-24 mice (P=0.019) and 3.1-fold larger in W-30 mice (P<0.001, n=10 per group). Mortality at 24 hours after hemorrhage induction was 0% in nonanticoagulated mice, 10% in W-24 mice, and 30% in W-30 mice. Hematoma enlargement between 2 and 24 hours after hemorrhage induction was −1.4% for nonanticoagulated mice, 22.9% for W-24 mice, and 62.2% for W-30 mice.
This study characterizes the first experimental model of W-ICH. It may be helpful in gaining further insights into the pathophysiology of W-ICH and may be used for testing the efficacy of treatment strategies, such as hemostatic therapy, in this severe subtype of stroke.
PMCID: PMC3712841  PMID: 18772448
cerebral hemorrhage; warfarin; mice
21.  The Relationship between Hematoma Iron Content and Perihematoma Edema: An MRI Study 
Iron neurotoxicity has been linked to delayed neuronal injury and edema formation after intracerebral hemorrhage (ICH). We have previously shown that serum ferritin, an indicator of body iron load, correlates with the relative perihematoma edema volume (RPHEV) on days 3–4 after ICH. We undertook this study to directly examine the relationship between in vivo brain and hematoma iron content, measured by MRI, and RPHEV.
We retrospectively reviewed prospectively collected clinical and laboratory data from 36 consecutive patients with acute spontaneous lobar ICH who had MRI performed within 2–4 days of ICH onset. We measured hematoma and edema volumes, and the signal intensity on T2-weighted images (T2SI), as an estimate of iron content, in the hematoma and contralateral globus pallidus (GP). We calculated the RPHEV and T2SI in the hematoma and GP, relative to T2SI in the frontal deep white matter which contains negligible iron, to estimate the hematoma and brain iron load. We used Spearman correlation coefficient to determine the association of relative T2SI of the hematoma and GP with RPHEV.
We found a significant inverse correlation between the relative T2SI in the hematoma (r = −0.75, p < 0.001) and to a lesser extent in the GP (r = −0.34, p = 0.04) and the RPHEV.
Our findings suggest that in vivo brain and hematoma iron content, as measured by MRI, is linked to perihematoma edema after ICH, and provide further support to existing preclinical evidence linking iron-mediated toxicity to delayed neuronal injury after ICH.
PMCID: PMC2914447  PMID: 19202331
Iron; Edema; Hematoma; Intracerebral hemorrhage; Magnetic resonance imaging
22.  Eight weeks of citicoline treatment does not perturb sleep/wake cycles in cocaine-dependent adults 
Citicoline (cytidine-5’-diphosphate) is a mononucleotide composed of ribose, cytosine, pyrophosphate, and choline, and is involved in the biosynthesis of the structural phosopholipids of cell membranes. Treatment with citicoline, improves memory in patients with dementia, and reduces damage to the brain after traumatic brain injury or stroke. Recent research has been conducted to assess whether citicoline is an effective treatment for cocaine dependence. In cocaine-dependent individuals, withdrawal from cocaine is associated with disturbed sleep, which may contribute to the high rate of relapse to cocaine use. Therefore, it is important to know the impact of citicoline on the sleep/wake cycle in these individuals in order to rate its overall efficacy.
In this double-blind, placebo-controlled trial, the effects of citicoline treatment on the sleep/wake cycles of cocaine dependent participants were assessed. The results of the current study are reported as part of a larger study, consisting of an eight-week treatment period to assess the efficacy of longer-term treatment with citicoline at decreasing cocaine consumption in cocaine-dependent polydrug using participants.
In this non-abstinent, cocaine-dependent population, citicoline had no effect on any of the sleep parameters measured including sleep efficiency, sleep latency, total sleep time, number of waking episodes, time awake per episode, amount of time in bed spent moving, number of sleep episodes, time asleep per episode, and amount of time in bed spent immobile.
These data suggest that eight weeks of citicoline administration does not disturb sleep/wake cycles of cocaine-dependent individuals.
PMCID: PMC3081995  PMID: 21397626
citicoline; CDP-choline; sleep; cocaine
23.  Prospective validation of the ICH Score for 12-month functional outcome 
Neurology  2009;73(14):1088-1094.
The ICH Score is a commonly used clinical grading scale for outcome after acute intracerebral hemorrhage (ICH) and has been validated for 30-day mortality, but not long-term functional outcome. The goals of this study were to assess whether the ICH Score accurately stratifies patients with regard to 12-month functional outcome and to further delineate the pace of recovery of patients during the first year post-ICH.
We performed a prospective observational cohort study of all patients with acute ICH admitted to the emergency departments of San Francisco General Hospital and UCSF Medical Center from June 1, 2001, through May 31, 2004. Components of the ICH Score (admission Glasgow Coma Scale score, initial hematoma volume, presence of intraventricular hemorrhage, infratentorial ICH origin, and age) were recorded along with other clinical characteristics. Patients were then assessed with the modified Rankin Scale (mRS) at hospital discharge, 30 days, and 3, 6, and 12 months post-ICH.
Of 243 patients, 95 (39%) died during initial acute hospitalization. The ICH Score accurately stratified patients with regard to 12-month functional outcome for various dichotomous cutpoints along the mRS (p < 0.05). Many patients continued to improve across the first year, with a small number of patients becoming disabled or dying due to late events unrelated to the initial ICH.
The ICH Score is a valid clinical grading scale for long-term functional outcome after acute intracerebral hemorrhage (ICH). Many ICH patients improve after hospital discharge and this improvement may continue even after 6 months post-ICH.
= Committee on Human Research;
= emergency department;
= Glasgow Coma Scale;
= intracerebral hemorrhage;
= intraventricular hemorrhage;
= modified Rankin Scale;
= San Francisco General Hospital.
PMCID: PMC2764394  PMID: 19726752
24.  Isoflurane Posttreatment Reduces Brain Injury After an Intracerebral Hemorrhagic Stroke in Mice 
Anesthesia and analgesia  2011;113(2):343-348.
Intracerebral hemorrhage (ICH) is a devastating stroke subtype affecting 120,000 Americans annually. Of those affected, 40-50% will die within the first thirty days, while the survivors are left with a lifetime of neurobehavioral disabilities. Recently, it has been shown that volatile anesthetics such as isoflurane can reduce brain injury after an ischemic stroke. As a result, in the present study, we investigated the effects of isoflurane as a posttreatment therapeutic modality in ICH-injured mice. Specifically investigating whether isoflurane posttreatment can preserve the structural integrity of the brain by reducing apoptotic damage and in turn, improve functional outcome by amelioration of brain edema and neurobehavioral deficits.
Male CD1 mice (n=53) were divided into the following groups: sham (n=14), ICH (n=14), ICH treated with 1.5% isoflurane posttreatment for 1 hour (n=15), and ICH treated with 1.5% isoflurane posttreatment for 2 hours (n=10). The blood injection ICH model was adapted; this involved extracting autologous blood from the mouse tail and injecting it directly into the right basal ganglia. One hour after surgery, treated mice were placed in a glass chamber maintained at 37°C and infused with 1.5% isoflurane for one or two hours. At 24hrs postinjury, mice were assessed for neurobehavioral deficits using the modified Garcia score and then sacrificed and assessed for brain water content. Double immunofluorescent staining was performed using neuronal marker MAP-2 and TUNEL under a fluorescent microscope to assess for apoptosis.
Our results indicated that after one hour 1.5% isoflurane posttreatment, there was a significant reduction in brain edema, a decrease in apoptotic cell death, and a significant improvement in neurobehavioral deficits.
Our results suggest that isoflurane may be an effective posttreatment therapeutic option for ICH because of its ability to reduce structural damage and subsequently preserve functional integrity.
PMCID: PMC3144303  PMID: 21596881
25.  The complement cascade as a therapeutic target in intracerebral hemorrhage 
Experimental neurology  2009;219(2):398-403.
Intracerebral hemorrhage (ICH) is the second most common and deadliest form of stroke. Currently, no pharmacologic treatment strategies exist for this devastating disease. Following the initial mechanical injury suffered at hemorrhage onset, secondary brain injury proceeds through both direct cellular injury and inflammatory cascades, which trigger infiltration of granulocytes and monocytes, activation of microglia, and disruption of the blood–brain barrier with resulting cerebral edema. The complement cascade has been shown to play a central role in the pathogenesis of secondary injury following ICH, although the specific mechanisms responsible for the proximal activation of complement remain incompletely understood. Cerebral injury following cleavage of complement component (C3) proceeds through parallel but interrelated pathways of anaphylatoxin-mediated inflammation and direct toxicity secondary to membrane attack complex-driven erythrocyte lysis. Complement activation also likely plays an important physiologic role in recovery following ICH. As such, a detailed understanding of the variation in functional effects of complement activation over time is critical to exploiting this target as an exciting translational strategy for intracerebral hemorrhage.
PMCID: PMC3731062  PMID: 19632224
Complement cascade; Edema; Hemoglobin; Intracerebral hemorrhage; Mechanism

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