Role of ferrous iron chelator 2,2′-dipyridyl in preventing delayed vasospasm in a primate model of subarachnoid hemorrhage

Horky, Laura L.; Pluta, Ryszard; Boock, Robert J.; Oldfield, Edward H.

doi:10.3171/jns.1998.88.2.0298

Cited by 70 publications

(51 citation statements)

References 40 publications

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“…However, it is unlikely that all the blood can be removed. Because in this phase of vasospasm, the dominant effect that has to be blocked is oxyhemoglobin neurotoxicity, chelation of ferrous iron of oxyhemoglobin by an intracellular Fe 2+ iron chelator such as dipyridyl has been proposed 33 . Eliminating ferrous hemoglobin by either or both of these methods may prevent neuronal apoptosis in the adventitia protecting a basic mechanism of the neuronal vasodilatory response 75,101 .…”

Section: Nnos Protectionmentioning

confidence: 99%

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: Nnos Protectionmentioning

confidence: 99%

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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“…In fact, studies in animals have been directed exclusively to the endpoint of VS reduction which, although important, may not represent the only criterion of interest. Several VS studies on deferoxamine in the rat femoral artery model (252,253), deferoxamine or deferiprone in rabbit cerebral arteries (254,255), and 2,2'-dipyridyl in primate cerebral arteries (256) have adduced evidence for an important activity of iron chelators against the development of VS. According to Horky et al (256), the chelator 2,2'-dipyridyl should be more efficient since the catalytic activity concerns the ferrous and not the ferric form of iron.…”

Section: -3 Iron Chelators and Other Anti-oxidantsmentioning

confidence: 99%

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Sercombe

Dinh

Gomis

2002

Japanese Journal of Pharmacology

184

140

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ABSTRACT-Aneurysmal subarachnoid hemorrhage frequently results in complications including intracranial hypertension, rebleeding and vasospasm. The extravasated blood is responsible for a cascade of reactions involving release of various vasoactive and pro-inflammatory factors (several of which are purported to induce vasospasm) from blood and vascular components in the subarachnoid space. The authors review the available evidence linking these factors to the development of inflammatory lesions of the cerebral vasculature, emphasizing: 1) neurogenic inflammation due to massive release of sensory nerve neuropeptides; 2) hemoglobin from lysed erythrocytes, which creates functional lesions of endothelial and smooth muscle cells; 3) activity, expression and metabolites of lipoxygenases cyclooxygenases and nitric oxide synthases; 4) the possible role of endothelin-1 as a pro-inflammatory agent; 5) serotonin, histamine and bradykinin which are especially involved in blood-brain barrier disruption; 6) the prothrombotic and pro-inflammatory action of complement and thrombin towards endothelium; 7) the multiple actions of activated platelets, including platelet-derived growth factor production; 8) the presence of perivascular and intramural macrophages and granulocytes and their interaction with adhesion molecules; 9) the evolution, origins, and effects of pro-inflammatory cytokines, especially IL-1, TNF-a and IL-6. Human and animal studies on the use of anti-inflammatory agents in subarachnoid hemorrhage include superoxide and other radical scavengers, lipid peroxidation inhibitors, iron chelators, NSAIDs, glucocorticoids, and serine protease inhibitors. Many animal studies claim reduced vasospasm, but these effects are not always confirmed in human trials, where symptomatic vasospasm and outcome are the major endpoints. Despite recent work on penetrating vessel constriction, there is a paucity of studies on inflammatory markers in the microcirculation.

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“…It is found that ferrous chelators, eg. Ebselen, Tililazad, Nicaraven and inhibitors of the enzymes producing free radicals, reduce the vasospasm on animal SAH models (7,8,9,14,19).…”

Section: Discussionmentioning

confidence: 99%

Dose dependent morphological effects of alpha lipoic acid on vasospastic femoral artery in rats

Ton¹,

Ovalıoğlu²,

Ton³

et al. 2012

Turkish Neurosurgery

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AIm:The dose dependent effects of alpha lipoic acid (α-LA) were investigated morphologically on rat vasospasm model. mAterIAl and methOds: 32 rats were divided into four groups: group I=control; group II=vasospasm; group III=vasospasm +low dose (20 mg/kg) intraperitoneal α-LA administered; and group IV=vasospasm +high dose (100 mg/kg) intraperitoneal α-LA administered. Histological and morphometric examinations were carried out for each groups under light microscope. results:The mean vascular wall thickness displayed significant increase in group II and III compared with group I (p<.05). Statistical comparison of group II and IV, regarding vascular wall thickness showed a significant decrease in group IV, and regarding vascular lumen area showed a significant increase in group IV (p<.05).COnClusIOn: It is demonstrated α-LA reduces the effects of vasospasm in high dose treatment group by decreasing the wall thickness and increasing the lumen surface area. The present study suggests that adequate dose of α-LA is a potential therapeutic agent in experimental vasospasm model. BulGulAr: Ana vasküler duvar kalınlığı grup II ve III'te grup I ile karşılaştırıldığında önemli bir artış göstermiştir (p<0,05). Grup II ve IV'ün istatistiksel olarak karşılaştırılması vasküler duvar kalınlığı açısından grup IV'te önemli bir azalma ve vasküler lümen açısından yine grup IV'te önemli bir artış göstermiştir (p<0,05). sOnuÇ: α-LA'nın yüksek doz tedavi grubunda duvar kalınlığını azaltıp lümen yüzey alanını arttırarak vazospazm etkilerini azalttığı gösterilmiştir. Mevcut çalışma yeterli dozda α-LA'nın deneysel bir vazospazm modelinde potansiyel bir terapötik ajan olduğunu düşündürmektedir.

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Role of ferrous iron chelator 2,2′-dipyridyl in preventing delayed vasospasm in a primate model of subarachnoid hemorrhage

Cited by 70 publications

References 40 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

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

Dose dependent morphological effects of alpha lipoic acid on vasospastic femoral artery in rats

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