Acta neurochirurgica. Supplement
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Acta Neurochir. Suppl. · Jan 2008
ReviewDysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH.
Nitric oxide (NO), also known as endothelium-derived relaxing factor, is produced by endothelial nitric oxide synthase (eNOS) in the intima and by neuronal nitric oxide synthase (nNOS) in the adventitia of cerebral vessels. It dilates the arteries in response to shear stress, metabolic demands, pterygopalatine ganglion stimulation, and chemoregulation. Subarachnoid haemorrhage (SAH) interrupts this regulation of cerebral blood flow. ⋯ CSF ADMA levels are closely associated with the degree and time-course of vasospasm; when CSF ADMA levels decrease, vasospasm resolves. Thus, the exogenous delivery of NO, inhibiting the L-arginine-methylating enzyme (IPRMT3) or stimulating DDAH II, may provide new therapeutic modalities to prevent and treat vasospasm. This paper will present results of preclinical studies supporting the NO-based hypothesis of delayed cerebral vasospasm development and its prevention by increased NO availability.
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Acta Neurochir. Suppl. · Jan 2008
ReviewNovel treatments for cerebral vasospasm following aneurysmal subarachnoid hemorrhage.
Cerebral vasospasm is a major cause of cerebral ischemia and poor outcomes in the setting of aneurysmal subarachnoid hemorrhage (SAH). Despite advances in diagnosis and treatment of SAH, the pathophysiology of vasospasm is still poorly understood and outcomes remain disappointing. Recent advances in understanding the role of hemoglobin in initiating an inflammatory cascade in the subarachnoid space open new avenues for therapy. Preliminary experimental and clinical evidence indicate that targets in the inflammatory and oxidative cascades hold promise in reducing the incidence and impact of cerebral vasospasm.
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Acta Neurochir. Suppl. · Jan 2008
ReviewVasospasm after aneurysmal subarachnoid hemorrhage: need for further study.
Cerebral vasospasm is the classic cause of delayed neurological deterioration leading to cerebral ischemia and infarction, and thus, poor outcome and occasionally death, after aneurysmal subarachnoid hemorrhage (SAH). Advances in diagnosis and treatment, principally nimodipine, intensive care management, hemodynamic manipulations, and endovascular neuroradiology procedures, have improved the prospects for these patients, but outcomes remain disappointing. A phase 2b clinical trial (CONSCIOUS-1) demonstrated marked prevention of vasospasm with the endothelin antagonist, clazosentan, yet patient outcome was not improved. ⋯ Clazosentan reduced angiographic vasospasm in a dose-dependent manner in patients with aneurysmal SAH following coiling or clipping of the aneurysm. Reducing the incidence of vasospasm should have an important effect on clinical outcome. A phase 3 clinical trial (CONSCIOUS-2) will focus on quantifying this outcome in patients undergoing aneurysm clipping receiving placebo or 5 mg/h of clazosentan.
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Intracerebral hemorrhage (ICH) is a subtype of stroke with very high mortality. Experiments have indicated that clot lysis and iron play an important role in ICH-induced brain injury. Iron overload occurs in the brain after ICH in rats. ⋯ Deferoxamine can rapidly penetrate the blood-brain barrier and accumulate in the brain tissue in significant concentration after systemic administration. We have demonstrated that deferoxamine reduces ICH-induced brain edema, neuronal death, brain atrophy, and neurological deficits. Iron chelation with deferoxamine could be a new therapy for ICH.