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.

TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice.

Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, exhibits the highest acute mortality and the worst long-term prognosis of all stroke subtypes. Unfortunately, treatment options for ICH are lacking due in part to a lack of feasible therapeutic targets. Inflammatory activation is associated with neurological deficits in pre-clinical ICH models and with patient deterioration after clinical ICH. In the present study, we tested the hypothesis that R-7050, a novel cell permeable triazoloquinoxaline inhibitor of the tumor necrosis factor receptor (TNFR) complex, attenuates neurovascular injury after ICH in mice. Up to 2h post-injury administration of R-7050 significantly reduced blood-brain barrier opening and attenuated edema development at 24h post-ICH. Neurological outcomes were also improved over the first 3 days after injury. In contrast, R-7050 did not reduce hematoma volume, suggesting the beneficial effects of TNFR inhibition were downstream of clot formation/resolution. These data suggest a potential clinical utility for TNFR antagonists as an adjunct therapy to reduce neurological injury and improve patient outcomes after ICH.

Attenuation of hematoma size and neurological injury with curcumin following intracerebral hemorrhage in mice.

OBJECT: Intracerebral hemorrhage (ICH) is associated with significant morbidity and mortality. Acute hematoma enlargement is an important predictor of neurological injury and poor clinical prognosis; but 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, the authors investigated whether the curry spice curcumin limited neurovascular injury following ICH in mice. METHODS: Intracerebral hemorrhage was induced in adult male CD-1 mice by 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. RESULTS: Curcumin increased hematoma resolution at 72 hours post-ICH. This effect was associated with a significant reduction in the expression of the proinflammatory mediators, tumor necrosis factor-α, interleukin-6, and interleukin-1ß. 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. CONCLUSIONS: 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.

Elucidating novel mechanisms of brain injury following subarachnoid hemorrhage: an emerging role for neuroproteomics.

Subarachnoid hemorrhage (SAH) is a devastating neurological injury associated with significant patient morbidity and death. Since the first demonstration of cerebral vasospasm nearly 60 years ago, the preponderance of research has focused on strategies to limit arterial narrowing and delayed cerebral ischemia following SAH. However, recent clinical and preclinical data indicate a functional dissociation between cerebral vasospasm and neurological outcome, signaling the need for a paradigm shift in the study of brain injury following SAH. Early brain injury may contribute to poor outcome and early death following SAH. However, elucidation of the complex cellular mechanisms underlying early brain injury remains a major challenge. The advent of modern neuroproteomics has rapidly advanced scientific discovery by allowing proteome-wide screening in an objective, nonbiased manner, providing novel mechanisms of brain physiology and injury. In the context of neurosurgery, proteomic analysis of patient-derived CSF will permit the identification of biomarkers and/or novel drug targets that may not be intuitively linked with any particular disease. In the present report, the authors discuss the utility of neuroproteomics with a focus on the roles for this technology in understanding SAH. The authors also provide data from our laboratory that identifies high-mobility group box protein-1 as a potential biomarker of neurological outcome following SAH in humans.

Curcumin attenuates vascular inflammation and cerebral vasospasm after subarachnoid hemorrhage in mice.

Cerebral vasospasm is a major cause of death and disability after subarachnoid hemorrhage (SAH); however, clinical therapies to limit the development of cerebral vasospasm are lacking. Although the causative factors underlying the development of cerebral vasospasm are poorly understood, oxidative stress contributes to disease progression. In the present study, curcumin (150 or 300 mg/kg) protected against the development of cerebral vasospasm and limited secondary cerebral infarction after SAH in mice. The protective effect of curcumin was associated with a significant attenuation of inflammatory gene expression and lipid peroxidation within the cerebral cortex and the middle cerebral artery. Despite the ability of curcumin to limit the development of cerebral vasospasm and secondary infarction, behavioral outcome was not improved, indicating a dissociation between cerebral vasospasm and neurologic outcome. Together, these data indicate a novel role for curcumin as a possible adjunct therapy after SAH, both to prevent the development of cerebral vasospasm and to reduce oxidative brain injury after secondary infarction.