Dissociation Between Vasospasm and Functional Improvement
Dissociation Between Vasospasm and Functional Improvement
Object: The efficacy of nimodipine was examined in a murine model of subarachnoid hemorrhage (SAH). End points included the diameter of the lumen of the middle cerebral artery (MCA) and behavioral outcome. An apolipo protein E (apoE)-mimetic peptide, acetyl-AS-Aib-LRKL-Aib-KRLL-amide, previously shown to have promise in this model was tested both alone and in combination with nimodipine. The effects of carboxyamidotriazole (CAI), a non-voltage-gated calcium channel blocker, were explored using the same animal paradigm.
Methods: Experimental SAH was induced in male C57B1/6J mice. For 3 days postoperatively, behavioral analyses were performed. In the first experiment, the mice were treated with vehicle or with low- or high-dose CAI for 3 days. In the second experiment, the mice were treated with vehicle, high- and low-dose nimo dipine, and/or the apoE-mimetic peptide. On postoperative Day 3 each mouse was killed and perfused. Following this, the right MCA was removed and its lumen measured.
Mice that received nimodipine demonstrated significant behavioral improvements when compared with vehicle-treat ed mice, but there was no clear dose-dependent effect on MCA diameter. Administration of the apoE-mimetic peptide was associated with improved functional performance and a significant reduction in vasospasm. Mice that received high-dose CAI performed worse on functional tests, despite a significant increase in the diameters of their MCA lumina.
Conclusions: These results demonstrate a dissociation between vasospasm and neurological outcomes that is consistent with findings of previous clinical trials.
Among patients who suffer SAH and survive the initial ictus, vasospasm remains the most feared medical complication. Vasospasm is a frequent source of secondary stroke and the delayed ischemic deficits that usually develop within the first 2 weeks after hemorrhage. At present, there are significant limitations to the treatment of aneurysmal SAH-induced cerebral vasospasm. Current therapeutic options include intracranial angioplasty, triple-H (hypervolemia, hemodilution, and hy pertension) therapy, and oral administration of nimodipine as vasospasm prophylaxis. However, because the majority of patients who suffer SAH either die or become permanently disabled, there is substantial room for improvement in treatment strategies for this group of patients.
Nimodipine was introduced as a therapeutic agent for the prophylaxis of vasospasm based on findings of a small randomized clinical trial in the US and a large trial in the United Kingdom. Both trials revealed modest improvements in neurological outcomes following nimodipine administration. Although the drug is accepted as the standard of care, the mechanism by which it works remains controversial. In addition to causing vascular relaxation, nimodipine may also serve as a neuroprotectant by blocking early neuronal calcium influx in the setting of acute ischemia. In fact, despite an improvement in functional outcome, no difference in angiographic vasospasm was observed between treatment and placebo in several trials. This is in contrast to the results of recent studies involving nicardipine, a similar dihydropyridine voltage-gated calcium channel blocker, which demonstrated improvements in angiographic vasospasm but no improvement in functional outcomes. The dissociation be tween angiographically confirmed vasospasm and functional improvement calls into question whether the effects of these calcium channel blockers are due to other mechanisms in addition to vasodilation, and whether surrogate radiographic evidence of vasospasm is appropriate as the sole clinical end point in early clinical trials.
Given our limited understanding of the pathophysiology of vasospasm and the pressing clinical need for more effective approaches, the use of clinically relevant animal models of SAH remains extremely important. A variety of animal models have been developed. Nosko and colleagues studied the effects of nimodipine on chronic vasospasm in monkeys and, using their model, produced results similar to those found in clinical trials. No difference in the incidence and severity of delayed vasospasm in a rabbit model was attributed to the use of nimodipine in a study in which dynamic perfusion computed tomography imaging was used. In both animal studies angiographically determined end points were used and the conclusions were similar to those of human clinical trials; how ever, neither study incorporated the behavioral outcomes of the animals, a limitation found in many studies involving animal models of SAH.
Recently, a murine model of SAH has been characterized that demonstrates evidence of vascular proliferation, lumen narrowing, and functional impairments. The clinical relevance of this model in testing new therapeutic approaches was suggested by the finding that the protective effects of simvastatin on murine vasospasm were readily translatable to the clinical arena. One advantage of using a murine model is the availability of transgenic technology that can be used to differentiate the molecular mechanisms of disease. For example, recent studies in volving endothelial nitric oxide synthase knockout transgenic animals demonstrated that the palliative effects of statins in the presence of SAH were dependent on upregulation of endothelial nitric oxide synthase.
Transgenic mice have also been used to study the role of genetic polymorphisms in recovery from neurological disease. For example, several recent clinical observations have associated the apoE isoform with outcomes after acute brain injury. Specifically, the presence of the apoE4 isoform is associated with increased incidences of vasospasm and worse outcome after aneurysmal SAH. These observations were replicated in a murine SAH model and led to the development of an apoE-based therapeutic intervention that improved histological and functional outcome.
As nimodipine is currently given as the standard drug of choice in patients with aneurysmal SAH, any new prospective therapy should be expected to provide additional benefit. To optimize the clinical relevance of our model, we sought to demonstrate whether nimodipine im proved functional and histological outcomes after SAH and whether the apoE-derived therapeutic peptide provided additional benefit over nimodipine alone. We also at tempted to characterize the relative importance of vas cular and neuroprotective effects by using CAI as a therapeutic intervention. Unlike nimodipine, CAI acts on non-voltage-gated calcium channels. This action would be expected to cause vasodilation in the absence of any direct neuronal effects. Carboxyamidotriazole also blocks the vas cular endothelial growth factor signaling cascade and has been studied as a potential oncological drug and as a treatment for retinopathy associated with prematurity. A lack of improvement in neurological outcome observed in the presence of an increased diameter of the MCA lumen would strengthen the hypothesis that direct neuroprotection is a relevant mechanism by which dihydropyridine calcium channel blockers improve neurological outcome after SAH.
Abstract and Introduction
Abstract
Object: The efficacy of nimodipine was examined in a murine model of subarachnoid hemorrhage (SAH). End points included the diameter of the lumen of the middle cerebral artery (MCA) and behavioral outcome. An apolipo protein E (apoE)-mimetic peptide, acetyl-AS-Aib-LRKL-Aib-KRLL-amide, previously shown to have promise in this model was tested both alone and in combination with nimodipine. The effects of carboxyamidotriazole (CAI), a non-voltage-gated calcium channel blocker, were explored using the same animal paradigm.
Methods: Experimental SAH was induced in male C57B1/6J mice. For 3 days postoperatively, behavioral analyses were performed. In the first experiment, the mice were treated with vehicle or with low- or high-dose CAI for 3 days. In the second experiment, the mice were treated with vehicle, high- and low-dose nimo dipine, and/or the apoE-mimetic peptide. On postoperative Day 3 each mouse was killed and perfused. Following this, the right MCA was removed and its lumen measured.
Mice that received nimodipine demonstrated significant behavioral improvements when compared with vehicle-treat ed mice, but there was no clear dose-dependent effect on MCA diameter. Administration of the apoE-mimetic peptide was associated with improved functional performance and a significant reduction in vasospasm. Mice that received high-dose CAI performed worse on functional tests, despite a significant increase in the diameters of their MCA lumina.
Conclusions: These results demonstrate a dissociation between vasospasm and neurological outcomes that is consistent with findings of previous clinical trials.
Introduction
Among patients who suffer SAH and survive the initial ictus, vasospasm remains the most feared medical complication. Vasospasm is a frequent source of secondary stroke and the delayed ischemic deficits that usually develop within the first 2 weeks after hemorrhage. At present, there are significant limitations to the treatment of aneurysmal SAH-induced cerebral vasospasm. Current therapeutic options include intracranial angioplasty, triple-H (hypervolemia, hemodilution, and hy pertension) therapy, and oral administration of nimodipine as vasospasm prophylaxis. However, because the majority of patients who suffer SAH either die or become permanently disabled, there is substantial room for improvement in treatment strategies for this group of patients.
Nimodipine was introduced as a therapeutic agent for the prophylaxis of vasospasm based on findings of a small randomized clinical trial in the US and a large trial in the United Kingdom. Both trials revealed modest improvements in neurological outcomes following nimodipine administration. Although the drug is accepted as the standard of care, the mechanism by which it works remains controversial. In addition to causing vascular relaxation, nimodipine may also serve as a neuroprotectant by blocking early neuronal calcium influx in the setting of acute ischemia. In fact, despite an improvement in functional outcome, no difference in angiographic vasospasm was observed between treatment and placebo in several trials. This is in contrast to the results of recent studies involving nicardipine, a similar dihydropyridine voltage-gated calcium channel blocker, which demonstrated improvements in angiographic vasospasm but no improvement in functional outcomes. The dissociation be tween angiographically confirmed vasospasm and functional improvement calls into question whether the effects of these calcium channel blockers are due to other mechanisms in addition to vasodilation, and whether surrogate radiographic evidence of vasospasm is appropriate as the sole clinical end point in early clinical trials.
Given our limited understanding of the pathophysiology of vasospasm and the pressing clinical need for more effective approaches, the use of clinically relevant animal models of SAH remains extremely important. A variety of animal models have been developed. Nosko and colleagues studied the effects of nimodipine on chronic vasospasm in monkeys and, using their model, produced results similar to those found in clinical trials. No difference in the incidence and severity of delayed vasospasm in a rabbit model was attributed to the use of nimodipine in a study in which dynamic perfusion computed tomography imaging was used. In both animal studies angiographically determined end points were used and the conclusions were similar to those of human clinical trials; how ever, neither study incorporated the behavioral outcomes of the animals, a limitation found in many studies involving animal models of SAH.
Recently, a murine model of SAH has been characterized that demonstrates evidence of vascular proliferation, lumen narrowing, and functional impairments. The clinical relevance of this model in testing new therapeutic approaches was suggested by the finding that the protective effects of simvastatin on murine vasospasm were readily translatable to the clinical arena. One advantage of using a murine model is the availability of transgenic technology that can be used to differentiate the molecular mechanisms of disease. For example, recent studies in volving endothelial nitric oxide synthase knockout transgenic animals demonstrated that the palliative effects of statins in the presence of SAH were dependent on upregulation of endothelial nitric oxide synthase.
Transgenic mice have also been used to study the role of genetic polymorphisms in recovery from neurological disease. For example, several recent clinical observations have associated the apoE isoform with outcomes after acute brain injury. Specifically, the presence of the apoE4 isoform is associated with increased incidences of vasospasm and worse outcome after aneurysmal SAH. These observations were replicated in a murine SAH model and led to the development of an apoE-based therapeutic intervention that improved histological and functional outcome.
As nimodipine is currently given as the standard drug of choice in patients with aneurysmal SAH, any new prospective therapy should be expected to provide additional benefit. To optimize the clinical relevance of our model, we sought to demonstrate whether nimodipine im proved functional and histological outcomes after SAH and whether the apoE-derived therapeutic peptide provided additional benefit over nimodipine alone. We also at tempted to characterize the relative importance of vas cular and neuroprotective effects by using CAI as a therapeutic intervention. Unlike nimodipine, CAI acts on non-voltage-gated calcium channels. This action would be expected to cause vasodilation in the absence of any direct neuronal effects. Carboxyamidotriazole also blocks the vas cular endothelial growth factor signaling cascade and has been studied as a potential oncological drug and as a treatment for retinopathy associated with prematurity. A lack of improvement in neurological outcome observed in the presence of an increased diameter of the MCA lumen would strengthen the hypothesis that direct neuroprotection is a relevant mechanism by which dihydropyridine calcium channel blockers improve neurological outcome after SAH.
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