The Effect of Levosimendan on Two Distinct Rodent Models of Parkinson’s Disease

Author(s): Amjad N. Abuirmeileh, Karem H. Alzoubi*, Abeer M. Rababa’h

Journal Name: Current Alzheimer Research

Volume 17 , Issue 11 , 2020


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Abstract:

Background: Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by motor symptoms related to the deficiency in dopamine levels, and cognitive symptoms that are similar in nature to those manifested during Alzheimer’s disease. Levosimendan, on the other hand, is a calcium sensitizer and phosphodiesterase inhibitor that was shown to possess neuroprotective, memoryenhancing, and anti-apoptotic properties.

Objective: In the current study, the possible protective effect of levosimendan was investigated in two animal models of Parkinson’s disease.

Methods: Both intracerebral injection 6-hydroxydopamine (6-OHDA) and the direct injection of lipopolysaccharide (LPS) into the substantia nigra were used as models to induce Parkinson’s-like behavior. Levosimendan (12 μg/kg intraperitoneally once weekly) was started 7 days before or 2 days after lesioning of the animals. At day 14 post-lesioning, animals were subjected to apomorphine challenge, which was correlated with dopamine levels in the striatum and tyrosine hydroxylase (TH)-positive nigral cells.

Results: Results showed that levosimendan restored the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells when administered 7 days before, but not two days after 6-OHDA lesioning. In the LPS model of PD, the number of rotations in the apomorphine challenge test, the levels of dopamine in the striatum, and the TH-positive nigral cells were restored when levosimendan was administered 7 days before as well as two days after lesioning.

Conclusion: Levosimendan seems to provide a promising agent with potential clinical value for PD.

Keywords: Parkinson's disease, 6-OHDA-induced rotations, levosemindan, LPS, immunostaining, striatum.

[1]
Dexter DT, Jenner P. Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 2013; 62: 132-44.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.01.018] [PMID: 23380027]
[2]
Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers 2017; 3: 17013.
[http://dx.doi.org/10.1038/nrdp.2017.13] [PMID: 28332488]
[3]
Litvan I, Chesselet MF, Gasser T, et al. The etiopathogenesis of Parkinson disease and suggestions for future research. Part II. J Neuropathol Exp Neurol 2007; 66(5): 329-36.
[http://dx.doi.org/10.1097/nen.0b013e318053716a] [PMID: 17483689]
[4]
Liu WM, Wu RM, Lin JW, Liu YC, Chang CH, Lin CH. Time trends in the prevalence and incidence of Parkinson’s disease in Taiwan: a nationwide, population-based study. J Formos Med Assoc 2016; 115(7): 531-8.
[http://dx.doi.org/10.1016/j.jfma.2015.05.014] [PMID: 26123636]
[5]
Frisardi V, Santamato A, Cheeran B. Parkinson’s disease: new insights into pathophysiology and rehabilitative approaches. Parkinsons Dis 2016; 20163121727
[http://dx.doi.org/10.1155/2016/3121727] [PMID: 27446627]
[6]
Tanaka S, Ishii A, Ohtaki H, Shioda S, Yoshida T, Numazawa S. Activation of microglia induces symptoms of Parkinson’s disease in wild-type, but not in IL-1 knockout mice. J Neuroinflammation 2013; 10: 143.
[http://dx.doi.org/10.1186/1742-2094-10-143] [PMID: 24289537]
[7]
Hirsch EC, Hunot S, Hartmann A. Neuroinflammatory processes in Parkinson’s disease. Parkinsonism Relat Disord 2005; 11(1): S9-S15.
[http://dx.doi.org/10.1016/j.parkreldis.2004.10.013] [PMID: 15885630]
[8]
Mattila PM, Rinne JO, Helenius H, Dickson DW, Röyttä M. Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson’s disease. Acta Neuropathol 2000; 100(3): 285-90.
[http://dx.doi.org/10.1007/s004019900168] [PMID: 10965798]
[9]
Sabbagh MN, Adler CH, Lahti TJ, et al. Parkinson disease with dementia: comparing patients with and without Alzheimer pathology. Alzheimer Dis Assoc Disord 2009; 23(3): 295-7.
[http://dx.doi.org/10.1097/WAD.0b013e31819c5ef4] [PMID: 19812474]
[10]
Davis AA, Inman CE, Wargel ZM, et al. APOE genotype regulates pathology and disease progression in synucleinopathy. Sci Transl Med 2020; 12(529)eaay3069
[http://dx.doi.org/10.1126/scitranslmed.aay3069] [PMID: 32024799]
[11]
Sabbagh MN, Silverberg N, Bircea S, et al. Is the functional decline of Parkinson’s disease similar to the functional decline of Alzheimer’s disease? Parkinsonism Relat Disord 2005; 11(5): 311-5.
[http://dx.doi.org/10.1016/j.parkreldis.2005.02.004] [PMID: 15886042]
[12]
Kovacs GG, Alafuzoff I, Al-Sarraj S, et al. Mixed brain pathologies in dementia: the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord 2008; 26(4): 343-50.
[http://dx.doi.org/10.1159/000161560] [PMID: 18849605]
[13]
Matthews FE, Brayne C, Lowe J, McKeith I, Wharton SB, Ince P. Epidemiological pathology of dementia: attributable-risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med 2009; 6(11)e1000180
[http://dx.doi.org/10.1371/journal.pmed.1000180] [PMID: 19901977]
[14]
Clinton LK, Blurton-Jones M, Myczek K, Trojanowski JQ, LaFerla FM. Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 2010; 30(21): 7281-9.
[http://dx.doi.org/10.1523/JNEUROSCI.0490-10.2010] [PMID: 20505094]
[15]
Lashley T, Holton JL, Gray E, et al. Cortical alpha-synuclein load is associated with amyloid-beta plaque burden in a subset of Parkinson’s disease patients. Acta Neuropathol 2008; 115(4): 417-25.
[http://dx.doi.org/10.1007/s00401-007-0336-0] [PMID: 18185940]
[16]
Pletnikova O, West N, Lee MK, et al. Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases. Neurobiol Aging 2005; 26(8): 1183-92.
[http://dx.doi.org/10.1016/j.neurobiolaging.2004.10.006] [PMID: 15917102]
[17]
Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 2003; 300(5619): 636-40.
[http://dx.doi.org/10.1126/science.1082324] [PMID: 12714745]
[18]
Kim KY, Lim SS, Kim HD, et al. Technology, Levosimendan compound for preventing or treating tau-related diseases US Patent (#9,962,384)2017; 61-75..
[19]
Rababa’h AM, Alzoubi KH, Atmeh A. Levosimendan enhances memory through antioxidant effect in rat model: behavioral and molecular study. Behav Pharmacol 2018; 29(4): 344-50.
[http://dx.doi.org/10.1097/FBP.0000000000000362] [PMID: 29176443]
[20]
Bin J, Wang Q, Zhuo YY, Xu JP, Zhang HT. Piperphentonamine (PPTA) attenuated cerebral ischemia-induced memory deficits via neuroprotection associated with anti-apoptotic activity. Metab Brain Dis 2012; 27(4): 495-505.
[http://dx.doi.org/10.1007/s11011-012-9330-x] [PMID: 22843383]
[21]
Papp Z, Édes I, Fruhwald S, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol 2012; 159(2): 82-7.
[http://dx.doi.org/10.1016/j.ijcard.2011.07.022] [PMID: 21784540]
[22]
Kelm RF, Wagenführer J, Bauer H, Schmidtmann I, Engelhard K, Noppens RR. Effects of levosimendan on hemodynamics, local cerebral blood flow, neuronal injury, and neuroinflammation after asphyctic cardiac arrest in rats. Crit Care Med 2014; 42(6): e410-9.
[http://dx.doi.org/10.1097/CCM.0000000000000308] [PMID: 24633188]
[23]
Björklund A, Dunnett SB. The amphetamine induced rotation test: a re-assessment of is use as a tool to monitor motor impairment and functional recovery in rodent models of Parkinson’s disease. J Parkinsons Dis 2019; 9(1): 17-29.
[http://dx.doi.org/10.3233/JPD-181525] [PMID: 30741691]
[24]
Pinter MM, Alesch F, Murg M, Helscher RJ, Binder H. Apomorphine test: a predictor for motor responsiveness to deep brain stimulation of the subthalamic nucleus. J Neurol 1999; 246(10): 907-13.
[http://dx.doi.org/10.1007/s004150050481] [PMID: 10552237]
[25]
Roehl AB, Hein M, Loetscher PD, et al. Neuroprotective properties of levosimendan in an in vitro model of traumatic brain injury. BMC Neurol 2010; 10: 97.
[http://dx.doi.org/10.1186/1471-2377-10-97] [PMID: 20964834]
[26]
Cameli M, Incampo E, Navarri R, et al. Effects of levosimendan in heart failure: the role of echocardiography. Echocardiography 2019; 36(8): 1566-72.
[http://dx.doi.org/10.1111/echo.14419] [PMID: 31287582]
[27]
Li J, Wang XY, Yang ZY, et al. The efficacy of simendan in the treatment of acute heart failure and its impact on NT-proBNP. Eur Rev Med Pharmacol Sci 2019; 23(9): 4027-32.
[PMID: 31115032]
[28]
Pathak A, Lebrin M, Vaccaro A, Senard JM, Despas F. Pharmacology of levosimendan: inotropic, vasodilatory and cardioprotective effects. J Clin Pharm Ther 2013; 38(5): 341-9.
[http://dx.doi.org/10.1111/jcpt.12067] [PMID: 23594161]
[29]
Efentakis P, Varela A, Chavdoula E, et al. Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose dependent manner: Implications for inotropy. Cardiovasc Res 2020; 116(3): 576-91.
[http://dx.doi.org/10.1093/cvr/cvz163] [PMID: 31228183]
[30]
Kocabeyoglu SS, Kervan U, Sert DE, et al. Optimization with levosimendan improves outcomes after left ventricular assist device implantation. Eur J Cardiothorac Surg 2020; 57(1): 176-82.
[http://dx.doi.org/10.1093/ejcts/ezz159] [PMID: 31155645]
[31]
Ørstavik Ø, Manfra O, Andressen KW, et al. The inotropic effect of the active metabolite of levosimendan, OR-1896, is mediated through inhibition of PDE3 in rat ventricular myocardium. PLoS One 2015; 10(3)e0115547
[http://dx.doi.org/10.1371/journal.pone.0115547] [PMID: 25738589]
[32]
Stępkowski TM, Wasyk I, Grzelak A, Kruszewski M. 6-OHDA-induced changes in Parkinson’s disease-related gene expression are not affected by the overexpression of PGAM5 in in vitro differentiated embryonic mesencephalic cells. Cell Mol Neurobiol 2015; 35(8): 1137-47.
[http://dx.doi.org/10.1007/s10571-015-0207-5] [PMID: 25986246]
[33]
Hernandez-Baltazar D, Zavala-Flores LM, Villanueva-Olivo A. The 6-hydroxydopamine model and parkinsonian pathophysiology: novel findings in an older model. Neurologia 2017; 32(8): 533-9.
[http://dx.doi.org/10.1016/j.nrl.2015.06.011] [PMID: 26304655]
[34]
Blum D, Torch S, Lambeng N, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 2001; 65(2): 135-72.
[http://dx.doi.org/10.1016/S0301-0082(01)00003-X] [PMID: 11403877]
[35]
Saito Y, Nishio K, Ogawa Y, et al. Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: involvement of hydrogen peroxide-dependent and -independent action. Free Radic Biol Med 2007; 42(5): 675-85.
[http://dx.doi.org/10.1016/j.freeradbiomed.2006.12.004] [PMID: 17291991]
[36]
Tronci E, Francardo V. Animal models of L-DOPA-induced dyskinesia: the 6-OHDA-lesioned rat and mouse. J Neural Transm (Vienna) 2018; 125(8): 1137-44.
[http://dx.doi.org/10.1007/s00702-017-1825-5] [PMID: 29242978]
[37]
Tieu K. A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harb Perspect Med 2011; 1(1)a009316
[http://dx.doi.org/10.1101/cshperspect.a009316] [PMID: 22229125]
[38]
Whitton PS. Neuroinflammation and the prospects for anti-inflammatory treatment of Parkinson’s disease. Curr Opin Investig Drugs 2010; 11(7): 788-94.
[PMID: 20571974]


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Article Details

VOLUME: 17
ISSUE: 11
Year: 2020
Page: [1043 - 1051]
Pages: 9
DOI: 10.2174/1567205017666201218102724
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