Beneficial effects of levosimendan on cerebral vasospasm induced by subarachnoid haemorrhage: An experimental study

Cengiz, Şahika Liva; Erdi, Mehmet Fatih; Tosun, Murat; Atalik, E. K.; Avunduk, Mustafa Cihat; Sönmez, Fatma Cavide; Mehmetoğlu, İdris; Baysefer, Alper

doi:10.3109/02699051003789260

Cited by 18 publications

(9 citation statements)

References 36 publications

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“…Thus, levosimendan should be able to prevent regional no-reflow and hyperperfusion. Moreover, studies have demonstrated an improvement in cerebral perfusion in critically ill infants with low cardiac output syndrome [23] as well as the prevention of vasospasm in an animal model of subarachnoid hemorrhage [24]. However, improved collateral perfusion by levosimendan could not be demonstrated during ischemia in the current investigation, which may indicate that effects on autoregulation during reperfusion play an important role in this model.…”

Section: Discussionmentioning

confidence: 55%

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Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model

et al. 2013

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BackgroundNeuroprotective strategies in ischemic stroke are an important challenge in clinical and experimental research as an adjunct to reperfusion therapy that may reduce neurologic injury and improve outcome. The neuroprotective properties of levosimendan in traumatic brain injury in vitro, transient global brain ischemia and focal spinal cord ischemia suggest the potential for similar effects in transient brain ischemia.MethodsTransient brain ischemia was induced for 60 min by intraluminal occlusion of the middle cerebral artery in 40 male Wistar rats under general anesthesia with s-ketamine and xylazine and with continuous monitoring of their blood pressure and cerebral perfusion. Five minutes before inducing reperfusion, a levosimendan bolus (24 μg kg -1) was administered over a 20 minute period. Infarct size, brain swelling, neurological function and the expression of inflammatory markers were quantified 24 hours after reperfusion.ResultsAlthough levosimendan limited the infarct size and brain swelling by 40% and 53%, respectively, no effect on neurological outcome or mortality could be demonstrated. Upregulation of tumor necrosis factor α and intercellular adhesion molecule 1 was significantly impeded. Cerebral blood flow during reperfusion was significantly reduced as a consequence of sustained autoregulation.ConclusionsLevosimendan demonstrated significant neuroprotective properties in a rat model of transient brain ischemia by reducing reperfusion injury.

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Section: Discussionmentioning

confidence: 55%

“…Possible targets may include the reduction of cerebral injury after resuscitation, ischemic stroke or cerebral vasospasm [24]. The cardioprotective properties may also be of interest as brain injury may induce heart failure [39].…”

Section: Discussionmentioning

confidence: 99%

Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model

et al. 2013

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“…Although levosimendan delayed reperfusion, we observed an upward shift in the relationship between CBF and MAP, which might counterbalance levosimendan’s direct protective actions. In this context the activation of mK ATP channels and increase of NO release in the vessels by levosimendan was effective and led to vasodilation in the brain as described earlier in an animal model of subarachnoid haemorrhage [42]. In addition, the delayed reperfusion during levosimendan treatment may explain the slower normalisation of the lactate/pyruvate ratio.…”

Section: Discussionmentioning

confidence: 69%

The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia

et al. 2012

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BackroundNeuroprotective strategies after cardiopulmonary resuscitation are currently the focus of experimental and clinical research. Levosimendan has been proposed as a promising drug candidate because of its cardioprotective properties, improved haemodynamic effects in vivo and reduced traumatic brain injury in vitro. The effects of levosimendan on brain metabolism during and after ischaemia/hypoxia are unknown.MethodsTransient cerebral ischaemia/hypoxia was induced in 30 male Wistar rats by bilateral common carotid artery clamping for 15 min and concomitant ventilation with 6% O2 during general anaesthesia with urethane. After 10 min of global ischaemia/hypoxia, the rats were treated with an i.v. bolus of 24 μg kg-1 levosimendan followed by a continuous infusion of 0.2 μg kg-1 min-1. The changes in the energy-related metabolites lactate, the lactate/pyruvate ratio, glucose and glutamate were monitored by microdialysis. In addition, the effects on global haemodynamics, cerebral perfusion and autoregulation, oedema and expression of proinflammatory genes in the neocortex were assessed.ResultsLevosimendan reduced blood pressure during initial reperfusion (72 ± 14 vs. 109 ± 2 mmHg, p = 0.03) and delayed flow maximum by 5 minutes (p = 0.002). Whereas no effects on time course of lactate, glucose, pyruvate and glutamate concentrations in the dialysate could be observed, the lactate/pyruvate ratio during initial reperfusion (144 ± 31 vs. 77 ± 8, p = 0.017) and the glutamate release during 90 minutes of reperfusion (75 ± 19 vs. 24 ± 28 μmol·L-1) were higher in the levosimendan group. The increased expression of IL-6, IL-1ß TNFα and ICAM-1, extend of cerebral edema and cerebral autoregulation was not influenced by levosimendan.ConclusionAlthough levosimendan has neuroprotective actions in vitro and on the spinal cord in vivo and has been shown to cross the blood–brain barrier, the present results showed that levosimendan did not reduce the initial neuronal injury after transient ischaemia/hypoxia.

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“…Neuronal apoptosis has been reported after CPB (27,28), and Levo has been shown in animal models to have antiapoptotic effects in the myocardium and brain, through its actions on mitochondrial ATP-dependent potassium channels (13,29,30). However, while apopotosis, as indicated by positive TUNEL staining, was present in all study groups, no significant difference was evident in its prevalence between groups.…”

Section: Brain Injury In a Model Of Infant Bypassmentioning

confidence: 80%

Impact of levosimendan on brain injury patterns in a lamb model of infant cardiopulmonary bypass

et al. 2014

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Background:The effects of levosimendan (Levo) on injury patterns in the immature brain following cardiopulmonary bypass (CPB) are unknown. Methods: Eighteen 3-to 4-wk-old anesthetized lambs, instrumented with vascular catheters and aortic and right carotid artery flow probes, were allocated to non-CPB, CPB, or CPB+Levo groups (each n = 6). After 120 min CPB with 90 min aortic cross-clamp, CPB animals received dopamine, and CPB+Levo animals both dopamine and Levo, for 4 h. All lambs then underwent brain magnetic resonance imaging, followed by postmortem brain perfusion fixation for immunohistochemical studies. results: In CPB lambs, aortic (P < 0.05) and carotid artery (P < 0.01) blood flows fell by 29 and 30%, respectively, between 2 and 4 h after cross-clamp removal but were unchanged in the CPB+Levo group. No brain injury was detectable with magnetic resonance imaging in either CPB or CPB+Levo lambs. However, on immunohistochemical analysis, white matter astrocyte density of both groups was higher than in non-CPB lambs (P < 0.05), while white matter microglial density was higher (P < 0.05), but markers of cortical oxidative stress were less prevalent in CPB+Levo than CPB lambs. conclusion: While Levo prevented early postoperative falls in cardiac output and carotid artery blood flow in a lamb model of infant CPB, this was associated with heterogeneous neuroglial activation and manifestation of markers of oxidative stress. n eurodevelopmental impairment affects up to one half of all survivors of infant heart surgery, with the spectrum ranging from gross and fine motor deficits, visuospatial difficulties, and impaired cognition to delay in speech and language development (1-5). The mechanisms contributing to brain injury in infants with congenital heart disease are complex and multifactorial, with no consistent improvement in neurodevelopmental outcomes achieved despite major advances in pediatric cardiac surgery and survival. A recent report from the Pediatric Heart Network and the National Heart, Lung, and Blood Institute working group reaffirmed the importance of trials aimed at evaluating novel therapies to address this problem (6).Younger infants undergoing surgery for congenital heart disease are most susceptible to developing brain injury (7,8).The perioperative interval represents a high-risk period with often extended duration of cardiopulmonary bypass (CPB) at the time of the first surgical procedure, as well as significant circulatory disturbance postoperatively. The avoidance of a low cardiac output (CO) state, which can complicate the postoperative course of a proportion of infants after cardiac surgery and which may contribute to later impairment, is a major focus of postoperative care after infant heart surgery. The PRIMACORP study demonstrated the efficacy of intravenous milrinone in preventing this phenomenon in a cohort of children undergoing intracardiac repairs (9). Our laboratory subsequently demonstrated that the inodilator levosimendan (Levo) (Simdax, Abbott, Botany, Australia) was at leas...

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Beneficial effects of levosimendan on cerebral vasospasm induced by subarachnoid haemorrhage: An experimental study

Cited by 18 publications

References 36 publications

Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model

Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model

The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia

Impact of levosimendan on brain injury patterns in a lamb model of infant cardiopulmonary bypass

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