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  • Author or Editor: Aij-Lie Kwan x
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Tomikatsu Toyoda, Aij-Lie Kwan, Murad Bavbek, Neal F. Kassell, John E. Wanebo and Kevin S. Lee

Object. Monophosphoryl lipid A (MPL) and diphosphoryl lipid (DPL) are derivatives of the lipopolysaccharide (endotoxin) of Salmonella minnesota strain R595. Monophosphoryl lipid A is relatively nontoxic and can stimulate the natural defense or immune system. Diphosphoryl lipid is relatively toxic; however, at higher concentrations, it can also stimulate an immune response. The purpose of the present study was to determine the effects of these endotoxin analogs on cerebral vasospasm after the onset of subarachnoid hemorrhage (SAH) in rabbits.

Methods. Intrathecal administration of MPL or DPL (5 µg/kg) was performed immediately before and 24 hours after induction of SAH in New Zealand White rabbits. Forty-eight hours after induction of SAH, the animals were killed by perfusion fixation for morphometric analyses of vessels or perfused with saline and assayed for superoxide dismutase (SOD) activity. Additional rabbits were administered MPL or DPL and killed 24 hours later for assessment of SOD activity; no SAH was induced in these animals.

Experimental SAH elicited spasm of the basilar arteries in each group. Vasospasm was markedly attenuated in animals treated with MPL (p < 0.01 compared with vehicle-treated animals), but not in animals treated with DPL. A substantial reduction in SOD activity in the basilar artery accompanied the vasospasm; this loss of activity was significantly blocked by treatment with MPL, but not DPL. In animals that were not subjected to experimental SAH, MPL elicited a significant increase in SOD activity over basal levels, whereas DPL was ineffective.

Conclusions. These data provide evidence of a marked protective effect of the endotoxin analog MPL against vasospasm. Although the mechanism(s) responsible for the protective effect of MPL remains to be verified, an enhancement of basal antioxidant activity and an inhibition of SAH-induced loss of this activity are attractive candidates. An MPL-based therapy could represent a useful addition to current therapies for SAH-induced cerebral injury.

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Hakan H. Caner, Aij-Lie Kwan, Adam Arthur, Arco Y. Jeng, Rodney W. Lappe, Neal F. Kassell and Kevin S. Lee

✓ The potent vasoconstrictor peptide, endothelin-1 (ET-1), has been implicated in the pathophysiology of cerebral vasospasm that occurs after subarachnoid hemorrhage (SAH). This peptide is synthesized as a large prepropeptide that requires a series of modifying steps for its activation. The last of these steps involves the proteolytic conversion of a relatively inactive propeptide, Big ET-1, to its active, 21—amino acid peptide form. The enzyme responsible for converting Big ET-1 to ET-1 is a metalloprotease called endothelin-converting enzyme (ECE). In the present study the authors examined the effects of a newly developed inhibitor of ECE on responses to ET peptides in the normal basilar artery and on pathophysiological constriction in the spastic basilar artery after SAH.

In the first series of experiments the authors examined normal basilar arteries in the rabbit, which were exposed transclivally and measured on-line using videomicroscopy. Intravenous administration or topical application of an active inhibitor of ECE, CGS 26303, blocked vasoconstrictor responses to topically applied Big ET-1 but not to ET-1. In contrast, topical application of a structurally related compound that does not inhibit ECE, CGS 24592, was ineffective in blocking vasoconstriction that was elicited by a topical application of Big ET-1. These findings indicate that CGS 26303 when administered systemically is capable of blocking the conversion of Big ET-1 to ET-1 in the basilar artery without affecting the ability of the vessel to respond to ET-1. In the second series of experiments the authors examined the effects of the ECE inhibitor on cerebral vasospasm after experimental SAH. Intraperitoneal administration of CGS 26303 via osmotic minipumps significantly attenuated the delayed spastic response of the basilar artery to an intracisternal injection of autologous blood.

This study provides the first evidence that systemic administration of an inhibitor of ECE is capable of preventing cerebral vasospasm after SAH. The results reinforce a growing body of evidence that ETs play a critical role in the development of spastic constriction after SAH. Moreover, the findings indicate that blocking the conversion of Big ET-1 to its active ET-1 form using CGS 26303 may represent a feasible strategy for ameliorating cerebral vasospasm.

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Aij-Lie Kwan, Murad Bavbek, Arco Y. Jeng, Wieslawa Maniara, Tomikatsu Toyoda, Rodney W. Lappe, Neal F. Kassell and Kevin S. Lee

✓ Delayed cerebral ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent vasoconstrictor peptide endothelin (ET) in the pathophysiology of cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting enzyme (ECE), CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits. Injections of CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy.

Treatment with CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of cerebral vasospasm. The ECE inhibitor CGS 26303 thus represents a promising therapeutic agent for the treatment of cerebral vasospasm following aneurysmal SAH.

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Barbara Cappelletto, Hakan H. Caner, Frank Schottler, Aij-Lie Kwan, David Eveleth, Patricia L. Foley, Neal F. Kassell and Kevin S. Lee

Calcium-activated proteolysis mediated by the protease inhibitor, calpain, has recently been implicated in the pathogenesis of cerebral vasospasm. The effect of one inhibitor of calcium-activated proteolysis, z-Leu-Phe-CONH-morpholene (zLF), on cerebrovascular constriction was examined in two experimental paradigms. In the first paradigm, the rabbit basilar artery (BA) was visualized via a transclival exposure, and its diameter was monitored using videomicroscopy. In the second experimental paradigm two intracisternal injections of autologous blood were administered to mimic a subarachnoid hemorrhage (SAH). The BA was visualized via the transclival exposure, and its luminal diameter was measured. Topical application of oxyhemoglobin (OxyHb), a known pathogenic agent in cerebral vasospasm, elicited vasoconstriction in normal animals, reducing arterial diameter to approximately 75% of resting levels. Pretreatment with zLF (100, 200, or 300 μM) attenuated vasoconstriction induced by OxyHb. In an experimental model of SAH, the diameter of the BA was reduced after the first injection of blood to approximately 67% of normal resting levels when measured 3 to 4 days later. This vasospastic response was reversed significantly by topical application of zLF (100 μM); vascular diameter was increased to approximately 84% of normal resting levels.

These findings demonstrate that both acute OxyHb-induced constriction and blood-induced vasospasm are sensitive to an inhibitor of the proteolytic enzyme, calpain. Together, these observations indicate an important role for calcium-activated proteolysis in the development and maintenance of vasospasm after SAH. In addition, it may be inferred from the data that inhibitors of calcium-activated proteolysis may be useful therapeutic agents for treating this form of cerebrovascular disease.