Delayed Intracranial Delivery of a Nitric Oxide Donor from a Controlled-release Polymer Prevents Experimental Cerebral Vasospasm in Rabbits

Pradilla, Gustavo; Thai, Quoc Anh; Legnani, Federico; Hsu, Wesley; Kretzer, Ryan M.; Wang, Paul P.; Tamargo, Rafael J.

doi:10.1227/01.neu.0000143615.26102.1a

Cited by 46 publications

(27 citation statements)

References 66 publications

(69 reference statements)

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“…This method was reported to prevent vasospasm with the NO donor and ibuprofen in a primate model of SAH but needs a further clinical confirmation 23,77 . The obvious disadvantage of this method is that it requires surgical access to the region of interest and with the rapidly increasing popularity of endovascular therapy 28,63 instead of surgical treatment for intracranial aneurysm, its use may be limited.…”

Section: No Delivery: Localmentioning

confidence: 94%

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

Pluta

2008

Acta Neurochirurgica Supplement

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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 hemorrhage (SAH) interrupts this regulation of cerebral blood flow. Hemoglobin, gradually released from erythrocytes in the subarachnoid space, destroys nNOS-containing neurons in the conductive arteries. This deprives the arteries of NO, leading to initiation of delayed vasospasm. But such vessel narrowing increases shear stress, which stimulates eNOS. This mechanism normally would lead to increased production of NO and dilation of arteries. However, a transient eNOS dysfunction evoked by an increase in the endogenous competitive NOS inhibitor, asymmetric dimethylarginine (ADMA), prevents this vasodilation. eNOS dysfunction has been recently shown to be evoked by increased levels of ADMA in cerebrospinal fluid (CSF) in response to the presence of bilirubin-oxidized fragments (BOXes). A direct cause of the increased ADMA CSF level is most likely decreased ADMA elimination owing to disappearance of ADMA-hydrolyzing enzyme [dimethylarginine dimethylaminohydrolase II (DDAH II)] immunoreactivity in the arteries in spasm. This eNOS dysfunction sustains vasospasm. CSF ADMA levels are closely associated with the degree and time course of vasospasm; when CSF ADMA levels decrease, vasospasm resolves. Thus, exogenous delivery of NO, inhibiting the L-arginine-methylating enzyme or stimulating DDAH II, may provide new therapeutic modalities to prevent and treat vasospasm. This paper will present results of pre-clinical studies supporting the NO-based hypothesis of delayed cerebral vasospasm development and its prevention by increased NO availability.

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Section: No Delivery: Localmentioning

confidence: 94%

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

Pluta

2008

Acta Neurochirurgica Supplement

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“…As a result, Hp 1-1 animals have only moderately reduced cerebral artery lumen patencies and usually minimal if any neurological deficits. 6,7,11 This absence of symptomatic vasospasm has been observed in several animal models, including monkeys, rabbits, rats, and mice. 6,7,11 Another potential limitation is that the time course of vasospasm differs between animals and humans.…”

Section: Chaichana Et Al Haptoglobin 2-2 Genotype Determines Vasospasmentioning

confidence: 90%

“…19 This Hp 2-2 genotypic association may also explain why animal models of SAH and vasospasm typically show vessel narrowing but often lack related neurological deficits. 6,7,11 The Hp 2-2 genotype exists only in humans, yet animals are universally Hp 1-1. 21 The Hp 1-1 protein product suppresses Hgb-induced inflammation more effectively than the Hp 2-2 protein product, 22,23,25,34 thereby reducing the inflammationassociated injury after blood injection.…”

Section: Chaichana Et Al Haptoglobin 2-2 Genotype Determines Vasospasmentioning

confidence: 99%

Haptoglobin 2-2 Genotype Determines Chronic Vasospasm After Experimental Subarachnoid Hemorrhage

Chaichana

Levy

Miller‐Lotan

et al. 2007

Stroke

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Background and Purpose-Chronic cerebral arterial vasospasm is the leading cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). Not all cases of SAH, however, develop chronic vasospasm. Inflammation, specifically leukocyte-endothelial cell interactions, appears to be critical in vasospasm development. Haptoglobin (Hp) is a serum protein that limits the extent of inflammation after a hemorrhagic event. An individual's Hp genotype may predict the severity of the inflammatory response during a hemorrhagic event, and consequently modulate the risk for vasospasm. Methods-Sixty mice (Hp 1-1, nϭ30; Hp 2-2, nϭ30) underwent injection of either autologous blood or normal saline solution into the cisterna magna. An additional 30 mice (15 per genotype) served as controls. The extent and manifestations of vasospasm were assessed by measuring lumen patency, quantifying activity levels, and counting the number of vessel-infiltrated macrophages/neutrophils at 24 hours after injection, which corresponds to the time of peak vasospasm in mice. Results-Genetically

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“…Sin embargo, la administración por vía intratecal de nitroprusiato de sodio, también un donador de NO, no mostró efectos positivos en otro estudio experimental, quizás debido a sus efectos tóxi-cos 51 . Es posible que otras vías de administración, como por ejemplo la incorporación a polímeros que permitan una liberación controlada, sea la alternativa adecuada 63 . Nuestro grupo en la Universidad de Berna pudo demostrar en un estudio experimental en conejos (Figura 2), que la administración intratecal de nitroglicerina, también donador de NO, causó una dilatación de la arteria basilar 30 .…”

Section: Donadores Del óXido Nítrico: Estatinas Y Medicamentos Intratunclassified

Perspectivas en el tratamiento del vasospasmo cerebral inducido por hemorragia subaracnoidea

et al. 2007

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ResumenEl vasospasmo cerebral sigue siendo la causa más importante de invalidez y muerte posterior a la ruptura de aneurismas saculares intracerebrales. Las estrategias terapéuticas en el vasospasmo inducido por la hemorragia subaracnoidea pueden ser agrupadas en cuatro categorías a saber: 1) terapias de prevención; 2) terapias de reversión; 3) terapias para el aumento de la perfusión cerebral; y 4) terapias de neuroprotección y rescate. Estudios experimentales recientes han permitido la realización de estudios clínicos fase II que sugieren resultados positivos con medicamentos que incluyen estatinas (simvastatina y pravastatina) y antagonistas de receptores tipo A de la endotelina-1 (clasozentan). De igual manera, evidencias experimentales y clínicas han mostrado las ventajas del drenaje de líquido cefalorraquídeo, administración intratecal de donadores de óxido nítrico, y los efectos desinhibidores de la Ca2+ Protein Kinasa C (Fasudil) y catecolaminas sobre la vascularización cerebral. Este artículo resume el estado de investigación actual de posibles agentes y estrategias terapéuticas relevantes en el tratamiento del vasospasmo cerebral. .. I would caution that vasospasm is still around, it is still alive and living in every neurosurgical unit. Hence my plea that our scientists not falter or lose interest for a final understanding and solution"C.G. Drake,1990 9

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Delayed Intracranial Delivery of a Nitric Oxide Donor from a Controlled-release Polymer Prevents Experimental Cerebral Vasospasm in Rabbits

Abstract: Delayed treatment of SAH with controlled-release DETA-NO polymers prevented experimental posthemorrhagic vasospasm in the rabbit. This inhibition was dose-dependent. This further confirms the role of NO in the pathogenesis of vasospasm.

Cited by 46 publications

References 66 publications

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

RETRACTED CHAPTER: Dysfunction of nitric oxide synthases as a cause and therapeutic target in delayed cerebral vasospasm after SAH

Haptoglobin 2-2 Genotype Determines Chronic Vasospasm After Experimental Subarachnoid Hemorrhage

Perspectivas en el tratamiento del vasospasmo cerebral inducido por hemorragia subaracnoidea

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