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

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Object. Oxyhemoglobin (HbO2) causes vasospasm after subarachnoid hemorrhage (SAH). The most likely spasmogenic component of HbO2 is iron. Various iron chelators, such as deferoxamine, have prevented vasospasm in vivo with limited success. However, only chelators of iron in the ferric state have been studied in animal models of vasospasm after SAH. Because free radical formation requires the ferrous (Fe++) moiety and Fe++ is a potent binder of the vasodilator nitric oxide, the authors hypothesized that iron in the ferrous state causes vasospasm and that chelators of Fe++, such as 2,2′-dipyridyl, may prevent vasospasm. This study was undertaken to investigate the influence of 2,2′-dipyridyl on vasospasm after induction of SAH in a primate model.

Methods. Twelve cynomolgus monkeys were randomly divided into two groups and then both groups underwent placement of an arterial autologous blood clot in the subarachnoid space around the right middle cerebral artery (MCA). The five animals in the control group received intravenously administered saline and the seven treated animals received intravenously administered chelator (2,2′-dipyridyl) for 14 days. Sequential arteriography for assessment of MCA diameter was performed before and on the 7th day after SAH.

Conclusions. Prevention of cerebral vasospasm by means of treatment with continuous intravenous administration of 2,2′-dipyridyl is reported in a primate model of SAH. This result provides insight into the possible mechanism of delayed vasospasm after aneurysmal SAH and provides a potential preventive therapy for it.

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Address reprint requests to: Edward H. Oldfield, M.D., Building 10, Room 5D-37, National Institutes of Health, Bethesda, Maryland 20892.

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    A: Bar graph showing the degree of vasospasm on Day 7 after SAH. Values represent the percentage decrease of the area of the proximal 14 mm of the right MCA on postoperative arteriograms (AP view) compared with preoperative values. The values presented are the mean ± the standard error of the mean of the decrease measured by three researchers working in a blinded fashion. The difference between control and treated monkeys is highly significant (p < 0.0001). The data from Monkey 7 (asterisk), which experienced impaired drug delivery, were excluded from this analysis. B: Graph showing the mean plasma iron concentration in the seven animals of the experimental group (115 ± 20 µg/ml, mean ± standard deviation) on Day 0. In the six monkeys that received 2,2′-dipyridyl, the levels dropped to 2 ± 2 µg/ml on Day 7 (p < 0.001). C: Graph showing the mean percentage transferrin saturation in the seven experimental monkeys (36 ± 5%) on Day 0, which dropped to −1.2 ± 2% on Day 7 in the six treated animals (p < 0.001). D: Bar graph showing 2,2′-dipyridyl levels in plasma in these six monkeys (< 1 µg/ml on Day 0 and 87 ± 68 mg/ml on Day 7). POD = postoperative day; R = right.

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