Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Neurology
Published in: BMC Neurology 1/2013

Open Access 01-12-2013 | Research article

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

Authors: Marc Hein, Norbert Zoremba, Chistian Bleilevens, Christian Bruells, Rolf Rossaint, Anna B Roehl

Published in: BMC Neurology | Issue 1/2013

Login to get access

Abstract

Background

Neuroprotective 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.

Methods

Transient 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.

Results

Although 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.

Conclusions

Levosimendan demonstrated significant neuroprotective properties in a rat model of transient brain ischemia by reducing reperfusion injury.
Appendix
Available only for authorised users
Literature
1.
Nogueira RG, Yoo AJ, Buonanno FS, Hirsch JA: Endovascular approaches to acute stroke, part 2: a comprehensive review of studies and trials. AJNR Am J Neuroradiol. 2009, 30: 859-875. 10.3174/ajnr.A1604.CrossRefPubMed
2.
Shuaib A, Butcher K, Mohammad AA, Saqqur M, Liebeskind DS: Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target. The Lancet Neurology. 2011, 10: 909-921. 10.1016/S1474-4422(11)70195-8.CrossRefPubMed
3.
Sutherland BA, Minnerup J, Balami JS, Arba F, Buchan AM, Kleinschnitz C: Neuroprotection for ischaemic stroke: translation from the bench to the bedside. Int J Stroke. 2012, 7: 407-418. 10.1111/j.1747-4949.2012.00770.x.CrossRefPubMed
4.
Durukan A, Tatlisumak T: Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav. 2007, 87: 179-197. 10.1016/j.pbb.2007.04.015.CrossRefPubMed
5.
Das B, Sarkar C: Pharmacological preconditioning by levosimendan is mediated by inducible nitric oxide synthase and mitochondrial KATP channel activation in the in vivo anesthetized rabbit heart model. Vascul Pharmacol. 2007, 47: 248-256. 10.1016/j.vph.2007.06.008.CrossRefPubMed
6.
Mayanagi K, Gaspar T, Katakam PV, Busija DW: Systemic administration of diazoxide induces delayed preconditioning against transient focal cerebral ischemia in rats. Brain Res. 2007, 1168: 106-111.CrossRefPubMed
7.
Lafci B, Yasa H, Ilhan G, Ortac R, Yilik L, Kestelli M, Goktogan T, Gurbuz A: Protection of the spinal cord from ischemia: comparative effects of levosimendan and iloprost. Eur Surg Res. 2008, 41: 1-7. 10.1159/000121394.CrossRefPubMed
8.
Katircioglu SF, Seren M, Parlar AI, Turan NN, Manavbasi Y, Aydog G, Cicekcioglu F, Tutun U, Ulus AT: Levosimendan effect on spinal cord ischemia-reperfusion injury following aortic clamping. J Card Surg. 2008, 23: 44-48. 10.1111/j.1540-8191.2007.00486.x.CrossRefPubMed
9.
Roehl AB, Hein M, Loetscher PD, Rossaint J, Weis J, Rossaint R, Coburn M: Neuroprotective properties of levosimendan in an in vitro model of traumatic brain injury. BMC Neurol. 2010, 10: 97-10.1186/1471-2377-10-97.CrossRefPubMedPubMedCentral
10.
Roehl AB, Zoremba N, Kipp M, Schiefer J, Goetzenich A, Bleilevens C, Kuhn-Velten N, Tolba R, Rossaint R, Hein M: The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia. BMC Neurol. 2012, 12: 81-10.1186/1471-2377-12-81.CrossRefPubMedPubMedCentral
11.
Hein M, Roehl AB, Baumert JH, Scherer K, Steendijk P, Rossaint R: Anti-ischemic effects of inotropic agents in experimental right ventricular infarction. Acta Anaesthesiol Scand. 2009, 53: 941-948. 10.1111/j.1399-6576.2009.01994.x.CrossRefPubMed
12.
Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council: Guide for the care and use of laboratory animals. 1996, Washington, D.C: National Academy Press, 7
13.
Bleilevens C, Roehl AB, Goetzenich A, Zoremba N, Kipp M, Dang J, Tolba R, Rossaint R, Hein M: Effect of anesthesia and cerebral blood flow on neuronal injury in a rat middle cerebral artery occlusion (MCAO) model. Exp Brain Res. 2013, 224: 155-164. 10.1007/s00221-012-3296-0.CrossRefPubMed
14.
Garcia JH, Wagner S, Liu KF, Hu XJ: Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke. 1995, 26: 627-634. 10.1161/01.STR.26.4.627.CrossRefPubMed
15.
Ryang Y, Dang J, Kipp M, Petersen K, Fahlenkamp AV, Gempt J, Wesp D, Rossaint R, Beyer C, Coburn M: Solulin reduces infarct volume and regulates gene-expression in transient middle cerebral artery occlusion in rats. BMC Neurosci. 2011, 12: 113-10.1186/1471-2202-12-113.CrossRefPubMedPubMedCentral
16.
Kramer M, Dang J, Baertling F, Denecke B, Clarner T, Kirsch C, Beyer C, Kipp M: TTC staining of damaged brain areas after MCA occlusion in the rat does not constrict quantitative gene and protein analyses. J Neurosci Methods. 2010, 187: 84-89. 10.1016/j.jneumeth.2009.12.020.CrossRefPubMed
17.
Robin E, Simerabet M, Hassoun SM, Adamczyk S, Tavernier B, Vallet B, Bordet R, Lebuffe G: Postconditioning in focal cerebral ischemia: role of the mitochondrial ATP-dependent potassium channel. Brain Res. 2011, 1375: 137-146.CrossRefPubMed
18.
Munakata H, Okada K, Hasegawa T, Hino Y, Kano H, Matsumori M, Okita Y: Controlled low-flow reperfusion after warm brain ischemia reduces reperfusion injury in canine model. Perfusion. 2010, 25: 159-168. 10.1177/0267659110370068.CrossRefPubMed
19.
Choi SK, Lee G, Choi S, Kim YJ, Park H, Park BJ: Neuroprotective effects by nimodipine treatment in the experimental global ischemic Rat model. Real time estimation of glutamate. J Korean Neurosurg Soc. 2011, 49: 1-10.3340/jkns.2011.49.1.1.CrossRefPubMedPubMedCentral
20.
Kang SW, Choi S, Park E, Chae S, Choi S, Jin Joo H, Lee G, Park H: Neuroprotective effects of magnesium-sulfate on ischemic injury mediated by modulating the release of glutamate and reduced of hyperreperfusion. Brain Res. 2011, 1371: 121-128.CrossRefPubMed
21.
Armstead WM, Kiessling JW, Riley J, Kofke WA, Vavilala MS: Phenylephrine infusion prevents impairment of ATP- and calcium-sensitive potassium channel-mediated cerebrovasodilation after brain injury in female, but aggravates impairment in male, piglets through modulation of ERK MAPK upregulation. J Neurotrauma. 2011, 28: 105-111. 10.1089/neu.2010.1581.CrossRefPubMedPubMedCentral
22.
Domoki F, Perciaccante JV, Veltkamp R, Bari F, Busija DW: Mitochondrial potassium channel opener diazoxide preserves neuronal-vascular function after cerebral ischemia in newborn pigs. Stroke. 1999, 30: 2713-2718. 10.1161/01.STR.30.12.2713. discussion 2718–9CrossRefPubMed
23.
Bravo MC, López P, Cabañas F, Pérez-Rodríguez J, Pérez-Fernández E, Pellicer A: Acute effects of levosimendan on cerebral and systemic perfusion and oxygenation in newborns: an observational study. Neonatology. 2011, 99: 217-223. 10.1159/000314955.CrossRefPubMed
24.
Liva Cengiz Ş, Fatih Erdi M, Tosun M, Atalik E, Cihat Avunduk M, Cavide Sönmez F, Mehmetoglu İ, Baysefer A: Beneficial effects of levosimendan on cerebral vasospasm induced by subarachnoid haemorrhage: an experimental study. Brain Inj. 2010, 24: 877-885. 10.3109/02699051003789260.CrossRef
25.
Dittmar M: External carotid artery territory ischemia impairs outcome in the endovascular filament model of middle cerebral artery occlusion in rats. Stroke. 2003, 34: 2252-2257. 10.1161/01.STR.0000083625.54851.9A.CrossRefPubMed
26.
Segreti JA, Marsh KC, Polakowski JS, Fryer RM: Evoked changes in cardiovascular function in rats by infusion of levosimendan, OR-1896 [(R)-N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide], OR-1855 [(R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one], dobutamine, and milrinone: comparative effects on peripheral resistance, cardiac output, dP/dt, pulse rate, and blood pressure. Journal of Pharmacology and Experimental Therapeutics. 2008, 325: 331-340. 10.1124/jpet.107.132530.CrossRefPubMed
27.
Zhu H, Luo W, Wang H: Iptakalim protects against hypoxic brain injury through multiple pathways associated with ATP-sensitive potassium channels. Neuroscience. 2008, 157: 884-894. 10.1016/j.neuroscience.2008.09.033.CrossRefPubMed
28.
Denes A, Ferenczi S, Kovacs KJ: Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood- brain barrier damage and brain oedema independently of infarct size. J Neuroinflammation. 2011, 8: 164-10.1186/1742-2094-8-164.CrossRefPubMedPubMedCentral
29.
Vemuganti R, Dempsey RJ, Bowen KK: Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke. 2004, 35: 179-184.CrossRefPubMed
30.
Xu X, Zhang S, Yan W, Li X, Zhang H, Zheng X: Development of cerebral infarction, apoptotic cell death and expression of X-chromosome-linked inhibitor of apoptosis protein following focal cerebral ischemia in rats. Life Sci. 2006, 78: 704-712. 10.1016/j.lfs.2005.05.080.CrossRefPubMed
31.
Timaru-Kast R, Wyschkon S, Luh C, Schaible E, Lehmann F, Merk P, Werner C, Engelhard K, Thal SC: Delayed inhibition of angiotensin II receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma. Crit Care Med. 2012, 40: 935-944. 10.1097/CCM.0b013e31822f08b9.CrossRefPubMed
32.
Sheng SP, Lei B, James ML, Lascola CD, Venkatraman TN, Jung JY, Maze M, Franks NP, Pearlstein RD, Sheng H, Warner DS: Xenon neuroprotection in experimental stroke. Anesthesiology. 2012, 117: 1262-1275. 10.1097/ALN.0b013e3182746b81.CrossRefPubMed
33.
Ulbrich C, Zendedel A, Habib P, Kipp M, Beyer C, Dang J: Long-term cerebral cortex protection and behavioral stabilization by gonadal steroid hormones after transient focal hypoxia. J Steroid Biochem Mol Biol. 2012, 131: 10-16. 10.1016/j.jsbmb.2012.01.007.CrossRefPubMed
34.
Haelewyn B, Rouillon C, Risso J, Abraini JH: Functional (neurologic) recovery following transient focal cerebral ischemia in the rat requires at least 80% of ipsilateral cortical and subcortical integrity. Exp Neurol. 2008, 213: 238-240. 10.1016/j.expneurol.2008.05.012.CrossRefPubMed
35.
David HN, Leveille F, Chazalviel L, MacKenzie ET, Buisson A, Lemaire M, Abraini JH: Reduction of ischemic brain damage by nitrous oxide and xenon. J Cereb Blood Flow Metab. 2003, 23: 1168-1173.CrossRefPubMed
36.
Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, Lo EH: Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009, 40: 2244-2250. 10.1161/STROKEAHA.108.541128.CrossRefPubMedPubMedCentral
37.
Encarnacion A, Horie N, Keren-Gill H, Bliss TM, Steinberg GK, Shamloo M: Long-term behavioral assessment of function in an experimental model for ischemic stroke. J Neurosci Methods. 2011, 196: 247-257. 10.1016/j.jneumeth.2011.01.010.CrossRefPubMedPubMedCentral
38.
Ström JO, Ingberg E, Theodorsson A, Theodorsson E: Method parameters’ impact on mortality and variability in rat stroke experiments: a meta-analysis. BMC Neurosci. 2013, 14: 41-10.1186/1471-2202-14-41.CrossRefPubMedPubMedCentral
39.
Yoshimura S, Toyoda K, Ohara T, Nagasawa H, Ohtani N, Kuwashiro T, Naritomi H, Minematsu K: Takotsubo cardiomyopathy in acute ischemic stroke. Ann Neurol. 2008, 64: 547-554. 10.1002/ana.21459.CrossRefPubMed
Metadata
Title
Levosimendan limits reperfusion injury in a rat middle cerebral artery occlusion (MCAO) model
Authors
Marc Hein
Norbert Zoremba
Chistian Bleilevens
Christian Bruells
Rolf Rossaint
Anna B Roehl
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Neurology / Issue 1/2013
Electronic ISSN: 1471-2377
DOI
https://doi.org/10.1186/1471-2377-13-106

Other articles of this Issue 1/2013

BMC Neurology 1/2013 Go to the issue

Case report

Encephalopathic Susac’s Syndrome associated with livedo racemosa in a young woman before the completion of family planning

Research article

Evaluation of an electronic diary for improvement of adherence to interferon beta-1b in patients with multiple sclerosis: design and baseline results of an observational cohort study

Research article

Diagnosis pathway for patients with amyotrophic lateral sclerosis: retrospective analysis of the US Medicare longitudinal claims database

Research article

The influence of Apolipoprotein E genotype on regional pathology in Alzheimer’s disease

Research article

An ultrasound model to calculate the brain blood outflow through collateral vessels: a pilot study

Research article

Cognitive profile in patients with a first-ever lacunar infarct with and without silent lacunes: a comparative study