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The Protective Effect of Safinamide in Ischemic Stroke Mice and a Brain Endothelial Cell Line

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Abstract

Stroke is one of the leading causes of mortality in cardiovascular diseases. The disruption of the brain-blood barrier is the common feature of stroke-related complications. Safinamide is a newly approved add-on drug to treat Parkinson’s disease, and previously studies suggest safinamide could have a potential role on neuroprotection. In this study, we investigated its preventive effect in both acutely induced stroke animals and brain endothelial cells. By the induction of middle cerebral artery occlusion (MCAO) in mice, we established a transit stroke model. Mice were administered 90 mg/kg/day safinamide prior to MCAO and during ischemia and reperfusion. Results indicate that the administration of safinamide significantly ameliorated MCAO-caused cerebral infarction volume, neurological deficit, disruption of the brain-blood barrier (BBB), and impaired expression of tight junction protein occludin and ZO-1. In cultured brain endothelial cell line bEND.3, pre-treatment with safinamide alleviated oxygen and glucose deprivation/reperfusion (OGD/R) caused cytotoxicity and favored cell survival. Transwell assay showed safinamide prevented OGD/R-induced hyperpermeability and the reduction of occludin and ZO-1. Moreover, safinamide treatment suppressed OGD/R-caused induction of metalloproteinase 2 (MMP-2) and 9 (MMP-9). Collectively, our data conclude safinamide has a preventive neuroprotection in acute stroke animals. The protective effect of safinamide on brain endothelial cells suggests the drug may ameliorate BBB disruption and improve vascular integrity in ischemia stroke.

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References

  • Abdullahi W, Tripathi D, Ronaldson PT (2018) Blood-brain barrier dysfunction in ischemic stroke: targeting tight junctions and transporters for vascular protection. Am J Physiol Cell Physiol 315(3):C343–C356

    Article  CAS  Google Scholar 

  • Blair HA, Dhillon S (2017) Safinamide: a review in Parkinson’s disease. CNS Drugs 31(2):169–176

    Article  CAS  Google Scholar 

  • Caccia C, Maj R, Calabresi M, Maestroni S, Faravelli L, Curatolo L, Salvati P, Fariello RG (2006) Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology 67(7 Suppl 2):S18–S23

    Article  CAS  Google Scholar 

  • Cheng J, Wen J, Wang N, Wang C, Xu Q, Yang Y (2019) Ion channels and vascular diseases. Arterioscler Thromb Vasc Biol 39(5):e146–e156

    Article  CAS  Google Scholar 

  • Deb P, Sharma S, Hassan KM (2010) Pathophysiologic mechanisms of acute ischemic stroke: an overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 17(3):197–218

    Article  CAS  Google Scholar 

  • Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371:1612–1623

    Article  CAS  Google Scholar 

  • Errington AC, Stöhr T, Lees G (2005) Voltage gated ion channels: targets for anticonvulsant drugs. Curr Top Med Chem 5(1):15–30

    Article  CAS  Google Scholar 

  • Fagan SC (2010) Drug repurposing for drug development in stroke. Pharmacotherapy 30(7 Pt 2):51S–54S

    Article  CAS  Google Scholar 

  • Fluri F, Schuhmann MK, Kleinschnitz C (2015) Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther 9:3445–3454

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gilbert G, Courtois A, Dubois M, Cussac LA, Ducret T, Lory P, Marthan R, Savineau JP, Quignard JF (2017) T-type voltage gated calcium channels are involved in endothelium-dependent relaxation of mice pulmonary artery. Biochem Pharmacol 138:61–72

    Article  CAS  Google Scholar 

  • Guan W, Kozak A, Fagan SC (2011) Drug repurposing for vascular protection after acute ischemic stroke. Acta Neurochir Suppl 111:295–298

    Article  Google Scholar 

  • Guo D, Liang S, Wang S, Tang C, Yao B, Wan W, Zhang H, Jiang H, Ahmed A, Zhang Z, Gu Y (2016) Role of epithelial Na+ channels in endothelial function. J Cell Sci 129(2):290–297

    Article  CAS  Google Scholar 

  • Li J, **ng S, Zhang J, Hong H, Yi L et al (2011) Decrease of tight junction integrity in the ipsilateral thalamus during the acute stage after focal infarction and ablation of the cerebral cortex in rats. Clin Exp Pharmacol Physiol 38(11):776–782

    Article  CAS  Google Scholar 

  • Li Y, Zhong W, Jiang Z, Tang X (2019) New progress in the approaches for blood-brain barrier protection in acute ischemic stroke. Brain Res Bull 144:46–57

    Article  CAS  Google Scholar 

  • Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20(1):84–91

    Article  CAS  Google Scholar 

  • Maj R, Fariello RG, Ukmar G, Varasi M, Pevarello P, McArthur RA, Salvati P (1998) PNU-151774E protects against kainate-induced status epilepticus and hippocampal lesions in the rat. Eur J Pharmacol 359(1):27–32

    Article  CAS  Google Scholar 

  • McCullough LD, Zeng Z, Blizzard KK, Debchoudhury I, Hurn PD (2005) Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J Cereb Blood Flow Metab 25:502–512

    Article  CAS  Google Scholar 

  • Moccia F, Berra-Romani R, Tanzi F (2012) Update on vascular endothelial Ca (2+) signalling: a tale of ion channels, pumps and transporters. World J Biol Chem 3(7):127–158

    Article  Google Scholar 

  • Morari M, Brugnoli A, Pisanò CA, Novello S, Caccia C, Melloni E, Padoani G, Vailati S, Sardina M (2018) Safinamide differentially modulates in vivo glutamate and GABA release in the rat hippocampus and basal ganglia. J Pharmacol Exp Ther 364(2):198–206

    Article  CAS  Google Scholar 

  • Sadeghian M, Mullali G, Pocock JM, Piers T, Roach A, Smith KJ (2016) Neuroprotection by safinamide in the 6-hydroxydopamine model of Parkinson’s disease. Neuropathol Appl Neurobiol 42(5):423–435

    Article  CAS  Google Scholar 

  • Salvador E, Burek M, Förster CY (2015) Stretch and/or oxygen glucose deprivation(OGD) in an in vitro traumatic brain injury (TBI) model induces calcium alteration and inflammatory cascade. Front Cell Neurosci 9:323

    PubMed  PubMed Central  Google Scholar 

  • Sturza A, Leisegang MS, Babelova A, Schröder K, Benkhoff S, Loot AE, Fleming I, Schulz R, Muntean DM, Brandes RP (2013) Monoamine oxidases are mediators of endothelial dysfunction in the mouse aorta. Hypertension 62(1):140–146

    Article  CAS  Google Scholar 

  • Tasker RC, Duncan ED (2015) Focal cerebral ischemia and neurovascular protection: a bench-to-bedside update. Curr Opin Pediatr 27(6):694–699

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Pharmacy, Luoyang Central Hospital Affiliated to Zhengzhou University, #288 Zhongzhou Middle Road, **gong District, Luoyang, 471009, Henan Province, China

    Tingting Xu, Rui Sun, Guoshi Wei & Shanshan Kong

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  1. Tingting Xu
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  2. Rui Sun
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  3. Guoshi Wei
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  4. Shanshan Kong
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Correspondence to Tingting Xu.

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All animals and protocols were used in accordance with the Institutional Animal Care and Use Committee of Affiliated Hospital of Zhengzhou University and National Health Commission of the People’s Republic of China Healthy Guide for the Care and Use of Laboratory Animals.

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Xu, T., Sun, R., Wei, G. et al. The Protective Effect of Safinamide in Ischemic Stroke Mice and a Brain Endothelial Cell Line. Neurotox Res 38, 733–740 (2020). https://doi.org/10.1007/s12640-020-00246-5

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  • DOI: https://doi.org/10.1007/s12640-020-00246-5

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