eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
vol. 15
Experimental research

Neuroprotective effects of the new Na channel blocker rs100642 in global ischemic brain injury

Suat Kamisli, Cenk Basaran, Kadir Batcioglu, Mustafa Namık Oztanir, Mehmet Gul, Basri Satilmis, Ayse Burcin Uyumlu, Basak Kayhan, Metin Genc

Arch Med Sci 2019; 15, 2: 467–474
Online publish date: 2019/03/04
View full text
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
RS100642, a mexiletine analogue, is a novel sodium channel blocker with neuroprotective and antioxidant activities. The protectivity of RS100642, which has been shown against focal cerebral ischemia, was investigated in global cerebral ischemia in this study.

Material and methods
Global cerebral ischemia was induced for five minutes in adult male Wistar Albino rats via the 4-vessel occlusion method. Intravenous administration of 1 mg/kg RS100642 following reperfusion for 30 min (RS100642 group) was compared with a sham treatment group (ischemia group) and nonischemized group (control) histologically based on morphology and caspase-3 immunohistochemistry, and biochemically based both on measurement of oxidative stress including malondialdehyde (MDA) levels, superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) activities and on assessment of apoptosis including caspase-3 and -8 activities and tumor necrosis factor α (TNF-α) levels at the end of 6 h.

While the RS100642 group had significantly lower MDA levels and higher SOD activities than the sham treatment group (p < 0.05), GPx and CAT activities of the RS100642 and sham treatment groups were similar (p > 0.05) and significantly lower than those of the controls (p < 0.05). Necrosis and caspase-3 activity and immunoreactivity in the RS100642 group were significantly lower than those in the sham treatment group (p < 0.05), while there was no significant difference between groups regarding caspase-8 and TNF-α (p > 0.05).

Na+ channel blockade by RS100642 has remarkable neuroprotective effects following global brain ischemia/reperfusion damage. Further research is required to determine the optimum dose and time of administration.


brain injury, global cerebral ischemia, sodium channels, neuroprotection

Sun J, Li T, Luan Q. Protective effects of delayed remote limb ischemic postconditioning: role for mitochondrial KATP channels in a rat model of focal cerebral ischemic reperfusion injury. J Cerebr Blood F Met 2012; 32: 851-9.
Distefano G, Pratico AD. Actualities on molecular pathogenesis and repairing processes of cerebral damage in perinatal hypoxic-ischemic encephalopathy. Ital J Pediatr 2010; 36: 63-72.
Lehotský J, Urban P, Pavlíková M. Molecular mechanisms leading to neuroprotection/ischemic tolerance: effect of preconditioning on the stress reaction of endoplasmic reticulum. Cell Mol Neurobiol 2009; 29: 917-25.
Woodruff TM, Thundyil J, Tang SC. Pathophysiology, treatment, and animal and cellular models of human ischemic stroke. Mol Neurodegener 2011; 6: 11-29.
Budihardjo I, Oliver H, Lutter M, Biochemical pathways of caspase activation during apoptosis. Cell Dev Biol 1999; 15: 269-90.
Linnik MD, Zobrist RH, Hatfield MD. Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 1993; 24: 2002-8.
Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 2010; 87: 779-89.
Ovbiagele B, Kidwell CS, Starkman S. Neuroprotective agents for the treatment of acute ischemic stroke. Curr Neurol Neurosci Rep 2003; 3: 9-20.
Williams AJ, Tortella FC. Neuroprotective effects of the sodium channel blocker RS100642 and attenuation of ischemia-induced brain seizures in the rat. Brain Res 2002; 932: 45-55.
Dave JR, Lin Y, Ved HS. RS-100642-198, a novel sodium channel blocker, provides differential neuroprotection against hypoxia/hypoglycemia, veratridine or glutamate-mediated neurotoxicity in primary cultures of rat cerebellar neurons. Neurotox Res 2001; 3: 381-95.
Williams AJ, Lu XCM, Hartings JA. Neuroprotection assessment by topographic electroencephalographic analysis: effects of a sodium channel blocker to reduce polymorphic delta activity following ischaemic brain injury in rats. Fundam Clin Pharmacol 2003; 17: 581-93.
Yao C, Williams AJ, Lu XCM. The sodium channel blocker RS100642 reverses down-regulation of the sodium channel alpha-subunit nav1.1 expression caused by transient ischemic brain injury in rats. Neurotox Res 2003; 5: 245-54.
Pulsinelli WA, Brierley JB. A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 1979; 10: 267-72.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951; 193: 265-75.
Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86: 271-8.
McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein. J Biol Chem 1969; 244: 6049-55.
Luck H. Catalase. In: Methods of Enzymatic Analysis. 2nd edn. Bergmeyer HU (ed). Academic Press/Verlag Chemie, New York 1963; 885-94.
Lawrence RA, Burk RF. GSH-Px activity in rat liver. Biochem Biophys Res Commun 1976; 71: 952-8.
Grafe MR, Woodworth KN, Noppens K. Long-term histological outcome after post-hypoxic treatment with 100% or 40% oxygen in a model of perinatal hypoxic-ischemic brain injury. Int J Dev Neurosci 2008; 26: 119-24.
Radovsky A, Katz L, Ebmeyer U. Ischemic neurons in rat brains after 6, 8, or 10 minutes of transient hypoxic ischemia. Toxicol Pathol 1997; 25: 500-5.
Budwit-Novotny DA, McCarty KS, Cox EB. Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res 1986; 46: 5419-25.
Ottani A, Vergoni AV, Saltini S. Effect of late treatment with gamma hydroxybutyrate on the histological and behavioral consequences of transient brain ischemia in the rat. Eur J Pharmacol 2004; 485: 183-91.
Simao F, Matte A, Matte C. Resveratrol prevents oxidative stress and inhibition of Na+K+-ATPase activity induced by transient global cerebral ischemia in rats. J Nutr Biochem 2011; 22: 921-8.
Back T, Hemmen T, Schuler OG. Lesion evolution in cerebral ischemia. J Neurol 2004; 251: 388-97.
Candelario-Jalil E, Mhadu NH, Al-Dalain SM. Time course of oxidative damage in different brain regions following transient cerebral ischemia in gerbils. Neurosci Res 2001; 41: 233-41.
White BC, Sullivan JM, DeGracia DJ. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 2000; 179 (Suppl 1-2): 1-33.
Kertmen H, Gürer B, Yilmaz ER. Antioxidant and antiapoptotic effects of darbepoetin-alpha against traumatic brain injury in rats. Arch Med Sci 2015; 11: 1119-28.
Björkman U, Ekholm R. Hydrogen peroxide degradation and glutathione peroxidase activity in cultures of thyroid cells. Mol Cell Endocrinol 1995; 111: 99-107.
Chelikani P, Fita I, Loewen PC. Diversity of structures and properties among catalases. Cell Mol Life Sci 2004; 61: 192-208.
Choi K, Kim J, Kim GW. Oxidative stress-induced necrotic cell death via mitochondira-dependent burst of reactive oxygen species. Curr Neurovasc Res 2009; 6: 213-22.
Clutton S. The importance of oxidative stress in apoptosis. Brit Med Bull 1997; 53: 662-8.
Lelli JL, Becks LL, Dabrowska MI. ATP converts necrosis to apoptosis in oxidant-injured endothelial cells. Free Radic Biol Med 1998; 25: 694-702.
Balla G, Vercellotti GM, Eaton JW. Iron loading of endothelial cell augments oxidant damage. J Lab Clin Med 1990; 116: 546-54.
Broughton BRS, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke 2009; 40: 331-9.
Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 2007; 54: 34-66.
Marton Z, Halmosi R, Horvath B. Scavenger effect of experimental and clinically used cardiovascular drugs. J Cardiovasc Pharmacol 2001; 38: 745-53.
Snider BJ, Gottron FJ, Choi DW. Apoptosis and necrosis in cerebrovascular disease. Oxidative/energy metabolism in neurodegenerative disorders. Ann NY Acad Sci 1999; 893: 243-53.
Cho S, Liu D, Gonzales C. Temporal assessment of caspase activation in experimental models of focal and global ischemia. Brain Res 2003; 982: 146-55.
Brahma MK, Dohare P, Varma S. The neuronal apoptotic death in global cerebral ischemia in gerbil: important role for sodium channel modulator. J Neurosci Res 2009; 87: 1400-11.
Namura S, Zhu J, Fink K. Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 1998; 18: 3659-68.
Uzar E, Acar A, Evliyaoğlu O. The anti-oxidant and anti-apoptotic effects of nebivolol and zofenopril in a model of cerebral ischemia/reperfusion in rats. Prog Neuropsychopharmacol Biol Psychiatry 2012; 36: 22-8.
Le DA, Wu Y, Huang Z. Caspase activation and neuroprotection in caspase-3 deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci 2002; 99: 15188-93.
Endres M, Namura S, Shimizu-Sasamata M. Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood F Met 1998; 18: 238-47.
Qian L, Flood PM, Hong JS. Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J Neural Transm 2010; 117: 971-9.
Nguyen TA, Frank-Cannon TC, Martinez TN, et al. Analysis of inflammation-related nigral degeneration and locomotor function in DJ-1-/- mice. J Neuroinflammation 2013; 10: 50-2.
Quick links
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe