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Effectiveness of arginase inhibitors against experimentally induced stroke

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Abstract

Stroke is a lethal disease, but it disables more than it kills. Stroke is the second leading cause of death and the most frequent cause of permanent disability in adults worldwide, with 90% of survivors having residual deficits. The pathophysiology of stroke is complex and involves a strong inflammatory response associated with oxidative stress and activation of several proteolytic enzymes. The current study was designed to investigate the effect of arginase inhibitors (L-citruline and L-ornithine) against ischemic stroke induced in rats by middle cerebral artery occlusion (MCAO). MCAO resulted in alteration in rat behavior, brain infarct, and edema associated with disruption of the blood-brain barrier (BBB). This was mediated through overexpression of arginase I and II, inducible NOS (iNOS), malondialdehyde (MDA), advanced glycation end products (AGEs), TNF-α, and IL-1β and downregulation of endothelial nitric oxide synthase (eNOS). Treatment with L-citruline and L-ornithine and the standard neuroprotective drug cerebrolysin ameliorated all the deleterious effects of stroke. These results indicate the possible use of arginase inhibitors in the treatment of stroke after suitable clinical trials are done.

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References

  • Aladag MA, Turkoz Y, Parlakpinar H, Ozen H, Egri M, Unal SC (2009) Melatonin ameliorates cerebral vasospasm after experimental subarachnoidal haemorrhage correcting imbalance of nitric oxide levels in rats. Neurochem Res 34(11):1935–1944

    Article  CAS  PubMed  Google Scholar 

  • Alvarez XA, Sampedro C, Cacabelos R, Linares C, Aleixandre M, Garcia-Fantini M et al (2009) Reduced TNF-alpha and increased IGF-I levels in the serum of Alzheimer’s disease patients treated with the neurotrophic agent cerebrolysin. Int J Neuropsychopharmacol 12(7):867–872

    Article  PubMed  Google Scholar 

  • Barakat W, Safwet N, El-Maraghy NN, Zakaria MN (2014) Candesartan and glycyrrhizin ameliorate ischemic brain damage through downregulation of the TLR signaling cascade. Eur J Pharmacol 724:43–50

    Article  CAS  PubMed  Google Scholar 

  • Barakat W, Fahmy A, Askar M (2015) Neuroprotective effect of L-Norvaline against ischemic brain damage in rats. Clinical Research and Development 2(3):117–128

  • Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17(3):472–476

    Article  CAS  PubMed  Google Scholar 

  • Berti R, Williams AJ, Moffett JR, Hale SL, Velarde LC, Elliott PJ, Yao C, Dave JR, Tortella FC (2002) Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia-reperfusion brain injury. J Cereb Blood Flow Metab 22(9):1068–1079

    Article  CAS  PubMed  Google Scholar 

  • Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nature reviews. Neuroscience 8(10):766–775

    CAS  PubMed  Google Scholar 

  • Caldwell RB, Zhang W, Romero MJ, Caldwell RW (2010) Vascular dysfunction in retinopathy—an emerging role for arginase. Brain Res Bull 81(2–3):303–309

    Article  CAS  PubMed  Google Scholar 

  • Caso JR, Lizasoain I, Lorenzo P, Moro MA, Leza JC (2006) The role of tumor necrosis factor-alpha in stress-induced worsening of cerebral ischemia in rats. Neuroscience 142(1):59–69

    Article  CAS  PubMed  Google Scholar 

  • Chang CI, Liao JC, Kuo L (1998) Arginase modulates nitric oxide production in activated macrophages. Am J Phys 274(1 Pt 2):H342–H348

    CAS  Google Scholar 

  • Cho SJ, Oh JY, Kim SO, Na S (2015) The effects of arginase inhibitor on lung oxidative stress and inflammation caused by pneumoperitoneum in rats. BMC Anesthesiol 15(1):1–9

    Article  Google Scholar 

  • Chung JH, Moon J, Lee YS, Chung HK, Lee SM, Shin MJ (2014) Arginase inhibition restores endothelial function in diet-induced obesity. Biochem Biophys Res Commun 451(2):179–183

    Article  CAS  PubMed  Google Scholar 

  • Ckless K, van der Vliet A, Janssen-Heininger Y (2007) Oxidative-nitrosative stress and post-translational protein modifications: implications to lung structure-function relations. Arginase modulates NF-kappaB activity via a nitric oxide-dependent mechanism. Am J Respir Cell Mol Biol 36(6):645–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cook NL, Kleinig TJ, Cvd H, Vink R (2010) Reference genes for normalising gene expression data in collagenase-induced rat intracerebral haemorrhage. BMC Mol Biol 11:7–7

    Article  PubMed  PubMed Central  Google Scholar 

  • Deb P, Sharma S, Hassan KM (2009) Pathophysiologic mechanisms of acute ischemic stroke: an overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 17(3):197–218

    Article  Google Scholar 

  • Donnan GA, Fisher M, Macleod M, Davis SM (2008) Stroke. Lancet 371(9624):1612–1623

    Article  CAS  PubMed  Google Scholar 

  • Durante W, Johnson FK, Johnson RA (2007) Arginase: a critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol 34(9):906–911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • El-Bassossy HM, El-Fawal R, Fahmy A (2012) Arginase inhibition alleviates hypertension associated with diabetes: effect on endothelial dependent relaxation and NO production. Vasc Pharmacol 57(5–6):194–200

    Article  CAS  Google Scholar 

  • Engel O, Kolodziej S, Dirnagl U, Prinz V (2011) Modeling stroke in mice—middle cerebral artery occlusion with the filament model. J Vis Exp 47:2423

    Google Scholar 

  • Esterbauer H (1996) Estimation of peroxidative damage. A critical review. Pathol Biol 44(1):25–28

    CAS  PubMed  Google Scholar 

  • Feng RUI, Zhang MIN, Wang X, Li W-B, Ren S-Q, Zhang F (2014) Pre-ischemic exercise alleviates oxidative damage following ischemic stroke in rats. Exp Ther Med 8(4):1325–1329

    Article  PubMed  PubMed Central  Google Scholar 

  • Forstermann U, Sessa WC (2012) Nitric oxide synthases: regulation and function. Eur Heart J 33(7):829–837

    Article  PubMed  Google Scholar 

  • Galler A, Müller G, Schinzel R, Kratzsch J, Kiess W, Münch G (2003) Impact of metabolic control and serum lipids on the concentration of advanced glycation end products in the serum of children and adolescents with type 1 diabetes, as determined by fluorescence spectroscopy and Nε-(carboxymethyl)lysine ELISA. Diabetes Care 26(9):2609–2615

    Article  CAS  PubMed  Google Scholar 

  • Gao X, Xu X, Belmadani S, Park Y, Tang Z, Feldman AM, Chilian WM, Zhang C (2007) TNF-alpha contributes to endothelial dysfunction by upregulating arginase in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol 27(6):1269–1275

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Bonilla L, Moore JM, Racchumi G, Zhou P, Butler JM, Iadecola C, Anrather J (2014) Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. J Immunol 193(5):2531–2537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Georgy GS, Nassar NN, Mansour HA, Abdallah DM (2013) Cerebrolysin ameloriates cognitive deficits in type III diabetic rats. PLoS One 8(6):e64847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerdemann A, Wagner Z, Solf A, Bahner U, Heidland A, Vienken J et al (2002) Plasma levels of advanced glycation end products during haemodialysis, haemodiafiltration and haemofiltration: potential importance of dialysate quality. Nephrol Dial Transplant 17(6):1045–1049

    Article  CAS  PubMed  Google Scholar 

  • Gronros J, Jung C, Lundberg JO, Cerrato R, Ostenson CG, Pernow J (2011) Arginase inhibition restores in vivo coronary microvascular function in type 2 diabetic rats. Am J Phys Heart Circ Phys 300(4):H1174–H1181

    Google Scholar 

  • Halliwell B (2009) The wanderings of a free radical. Free Radic Biol Med 46(5):531–542

    Article  CAS  PubMed  Google Scholar 

  • Hamann M, Rossi DJ, Marie H, Attwell D (2002) Knocking out the glial glutamate transporter GLT-1 reduces glutamate uptake but does not affect hippocampal glutamate dynamics in early simulated ischaemia. Eur J Neurosci 15(2):308–314

    Article  PubMed  Google Scholar 

  • Hein TW, Zhang C, Wang W, Chang CI, Thengchaisri N, Kuo L (2003) Ischemia-reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J 17(15):2328–2330

    Article  CAS  PubMed  Google Scholar 

  • Helmersson J, Vessby B, Larsson A, Basu S (2004) Association of type 2 diabetes with cyclooxygenase-mediated inflammation and oxidative stress in an elderly population. Circulation 109(14):1729–1734

    Article  CAS  PubMed  Google Scholar 

  • Hink U, Li H, Mollnau H, Oelze M, Matheis E, Hartmann M, Skatchkov M, Thaiss F, Stahl RAK, Warnholtz A, Meinertz T, Griendling K, Harrison DG, Forstermann U, Munzel T (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88(2):E14–E22

    Article  CAS  PubMed  Google Scholar 

  • Horowitz S, Binion DG, Nelson VM, Kanaa Y, Javadi P, Lazarova Z et al (2007) Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 292(5):11

    Article  Google Scholar 

  • Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17(7):796–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iadecola C, Zhang F, Xu S, Casey R, Ross ME (1995a) Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab 15(3):378–384

    Article  CAS  PubMed  Google Scholar 

  • Iadecola C, Zhang F, Xu X (1995b) Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am J Phys 268(1 Pt 2):R286–R292

    CAS  Google Scholar 

  • Ikeda T, Maruyama K, Ito N, Utagawa A, Nagane M, Shiokawa Y (2012) Serum pentosidine, an advanced glycation end product, indicates poor outcomes after acute ischemic stroke. J Stroke Cerebrovasc Dis 21(5):386–390

    Article  PubMed  Google Scholar 

  • Ingaramo PI, Ronco MT, Frances DE, Monti JA, Pisani GB, Ceballos MP et al (2011) Tumor necrosis factor alpha pathways develops liver apoptosis in type 1 diabetes mellitus. Mol Immunol 48(12–13):1397–1407

    Article  CAS  PubMed  Google Scholar 

  • Jin X-Q, Ye F, Zhang J-J, Zhao Y, Zhou X-L (2015) Triptolide attenuates cerebral ischemia and reperfusion injury in rats through the inhibition the nuclear factor kappa B signaling pathway. Neuropsychiatr Dis Treat 11:1395–1403

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kelleher ZT, Matsumoto A, Stamler JS, Marshall HE (2007) NOS2 regulation of NF-kappaB by S-nitrosylation of p65. J Biol Chem 282(42):30667–30672

    Article  CAS  PubMed  Google Scholar 

  • Koizumi J, Yoshida Y, Nakazawa TGO (1986) Experimental studies of ischemic brain edema, I: a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke 8:1–8

    Article  Google Scholar 

  • Kozak W, Kozak A, Johnson MH, Elewa HF, Fagan SC (2008) Vascular protection with candesartan after experimental acute stroke in hypertensive rats: a dose-response study. J Pharmacol Exp Ther 326(3):773–782

    Article  CAS  PubMed  Google Scholar 

  • Lee KE, Kang YS (2017) Characteristics of L-citrulline transport through blood-brain barrier in the brain capillary endothelial cell line (TR-BBB cells). J Biomed Sci 24(1):28

    Article  PubMed  PubMed Central  Google Scholar 

  • Li ST, Pan J, Hua XM, Liu H, Shen S, Liu JF, Li B, Tao BB, Ge XL, Wang XH, Shi JH, Wang XQ (2014) Endothelial nitric oxide synthase protects neurons against ischemic injury through regulation of brain-derived neurotrophic factor expression. CNS Neurosci Ther 20(2):154–164

    Article  CAS  PubMed  Google Scholar 

  • Liang CJ, Wang SH, Chen YH, Chang SS, Hwang TL, Leu YL, Tseng YC, Li CY, Chen YL (2011) Viscolin reduces VCAM-1 expression in TNF-alpha-treated endothelial cells via the JNK/NF-kappaB and ROS pathway. Free Radic Biol Med 51(7):1337–1346

    Article  CAS  PubMed  Google Scholar 

  • Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC et al (1994) Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25(7):1481–1488

    Article  CAS  PubMed  Google Scholar 

  • Liu P, Smith PF, Appleton I, Darlington CL, Bilkey DK (2004) Potential involvement of NOS and arginase in age-related behavioural impairments. Exp Gerontol 39(8):1207–1222

    Article  CAS  PubMed  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  PubMed  Google Scholar 

  • Manaenko A, Chen H, Kammer J, Zhang JH, Tang J (2011) Comparison Evans blue injection routes: intravenous vs. intraperitoneal, for measurement of blood-brain barrier in a mice hemorrhage model. J Neurosci Methods 195(2):206–210

    Article  PubMed  Google Scholar 

  • Masliah E, Diez-Tejedor E (2012) The pharmacology of neurotrophic treatment with cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders. Drugs Today (Barcelona, Spain : 1998) 48(Suppl A):3–24

    CAS  Google Scholar 

  • Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M et al (2016) Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation 133(4):e38–e360

    Article  PubMed  Google Scholar 

  • Muley MM, Thakare VN, Patil RR, Kshirsagar AD, Naik SR (2012) Silymarin improves the behavioural, biochemical and histoarchitecture alterations in focal ischemic rats: a comparative evaluation with piracetam and protocatachuic acid. Pharmacol Biochem Behav 102(2):286–293

    Article  CAS  PubMed  Google Scholar 

  • Munch G, Keis R, Wessels A, Riederer P, Bahner U, Heidland A et al (1997) Determination of advanced glycation end products in serum by fluorescence spectroscopy and competitive ELISA. Eur J Clin Chem Clin Biochem 35(9):669–677

    CAS  PubMed  Google Scholar 

  • Namura S, Ooboshi H, Liu J, Yenari MA (2013) Neuroprotection after cerebral ischemia. Ann N Y Acad Sci 1278:25–32. https://doi.org/10.1111/nyas.12087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nathan C (1997) Inducible nitric oxide synthase: what difference does it make? J Clin Invest 100(10):2417–2423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nat Med 19(12):1584–1596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Onose G, Mureşanu DF, Ciurea AV, Chendreanu CD, Mihaescu AS, Mardare DC et al (2009) Neuroprotective and consequent neurorehabilitative clinical outcomes, in patients treated with the pleiotropic drug cerebrolysin. J Med Life 2(4):350–360

    CAS  PubMed  PubMed Central  Google Scholar 

  • Panahpour H, Nekooeian AA, Dehghani GA (2007) Quantitative evaluation of blood brain barrier permeability in transient focal cerebral ischemia in the rat. Physiol Pharmacol 11(2):99–106

    Google Scholar 

  • Pannu R, Singh I (2006) Pharmacological strategies for the regulation of inducible nitric oxide synthase: neurodegenerative versus neuroprotective mechanisms. Neurochem Int 49(2):170–182

    Article  CAS  PubMed  Google Scholar 

  • Patockova J, Krsiak M, Marhol P, Tumova E (2003) Cerebrolysin inhibits lipid peroxidation induced by insulin hypoglycemia in the brain and heart of mice. Physiol Res 52(4):455–460

    CAS  PubMed  Google Scholar 

  • Pernow J, Jung C (2013) Arginase as a potential target in the treatment of cardiovascular disease: reversal of arginine steal? Cardiovasc Res 98(3):334–343

    Article  CAS  PubMed  Google Scholar 

  • Pokrovskiy MV, Korokin MV, Tsepeleva SA, Pokrovskaya TG, Gureev VV, Konovalova EA et al (2011) Arginase inhibitor in the pharmacological correction of endothelial dysfunction. Int J Hypertens 2011:515047

    Article  PubMed  PubMed Central  Google Scholar 

  • Prieto CP, Krause BJ, Quezada C, San Martin R, Sobrevia L, Casanello P (2011) Hypoxia-reduced nitric oxide synthase activity is partially explained by higher arginase-2 activity and cellular redistribution in human umbilical vein endothelium. Placenta 32(12):932–940

    Article  CAS  PubMed  Google Scholar 

  • Reglodi D, Tamas A, Lengvari I (2003) Examination of sensorimotor performance following middle cerebral artery occlusion in rats. Brain Res Bull 59(6):459–466

    Article  CAS  PubMed  Google Scholar 

  • Ren J, Sietsma D, Qiu S, Moessler H, Finklestein SP (2007) Cerebrolysin enhances functional recovery following focal cerebral infarction in rats. Restor Neurol Neurosci 25(1):25–31

    CAS  PubMed  Google Scholar 

  • Romero MJ, Platt DH, Tawfik HE, Labazi M, El-Remessy AB, Bartoli M et al (2008) Diabetes-induced coronary vascular dysfunction involves increased arginase activity. Circ Res 102(1):95–102

    Article  CAS  PubMed  Google Scholar 

  • Ryoo S, Berkowitz DE, Lim HK (2011) Endothelial arginase II and atherosclerosis. Korean J Anesthesiol 61(1):3–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schroeter M, Küry P, Jander S (2003) Inflammatory gene expression in focal cortical brain ischemia: differences between rats and mice. Mol Brain Res 117(1):1–7

    Article  CAS  PubMed  Google Scholar 

  • Senda DM, Franzin S, Mori MA, de Oliveira RM, Milani H (2011) Acute, post-ischemic sensorimotor deficits correlate positively with infarct size but fail to predict its occurrence and magnitude after middle cerebral artery occlusion in rats. Behav Brain Res 216(1):29–35

    Article  PubMed  Google Scholar 

  • Shichita T, Sakaguchi R, Suzuki M, Yoshimura A (2012) Post-ischemic inflammation in the brain. Front Immunol 3:132

    Article  PubMed  PubMed Central  Google Scholar 

  • Singh VP, Bali A, Singh N, Jaggi AS (2014) Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 18(1):1–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strong K, Mathers C, Bonita R (2007) Preventing stroke: saving lives around the world. Lancet Neurol 6(2):182–187

    Article  PubMed  Google Scholar 

  • Taki FA, Abdel-Rahman AA, Zhang B (2014) A comprehensive approach to identify reliable reference gene candidates to investigate the link between alcoholism and endocrinology in Sprague-Dawley rats. PLoS One 9(5):e94311

    Article  PubMed  PubMed Central  Google Scholar 

  • Thengchaisri N, Hein TW, Wang W, Xu X, Li Z, Fossum TW et al (2006) Upregulation of arginase by H2O2 impairs endothelium-dependent nitric oxide-mediated dilation of coronary arterioles. Arterioscler Thromb Vasc Biol 26(9):2035–2042

    Article  CAS  PubMed  Google Scholar 

  • Thichanpiang P, Harper SJ, Wongprasert K, Bates DO (2014) TNF-alpha-induced ICAM-1 expression and monocyte adhesion in human RPE cells is mediated in part through autocrine VEGF stimulation. Mol Vis 20:781–789

    PubMed  PubMed Central  Google Scholar 

  • Wang C-C, Chio C-C, Chang C-H, Kuo J-R, Chang C-P (2010) Beneficial effect of agmatine on brain apoptosis, astrogliosis, and edema after rat transient cerebral ischemia. BMC Pharmacol 10:11–11

    Article  PubMed  PubMed Central  Google Scholar 

  • Yabuki Y, Shioda N, Yamamoto Y, Shigano M, Kumagai K, Morita M, Fukunaga K (2013) Oral L-citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection. Brain Res 1520:157–167

    Article  CAS  PubMed  Google Scholar 

  • You H, Gao T, Cooper TK, Morris SM, Awad AS (2013) Arginase inhibition mediates renal tissue protection in diabetic nephropathy by a nitric oxide synthase 3-dependent mechanism. Kidney Int 84(6):1189–1197. https://doi.org/10.1038/ki.2013.1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Iyer RK, Kern RM, Rodriguez WI, Grody WW, Cederbaum SD (2001) Expression of arginase isozymes in mouse brain. J Neurosci Res 66(3):406–422

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Baban B, Rojas M, Tofigh S, Virmani SK, Patel C, Behzadian MA, Romero MJ, Caldwell RW, Caldwell RB (2009) Arginase activity mediates retinal inflammation in endotoxin-induced uveitis. Am J Pathol 175(2):891–902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ (2000) Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 10(1):95–112

    Article  PubMed  Google Scholar 

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Funding

This study was funded by the University of Tabuk, Kingdom of Saudi Arabia (S-1438-0096) to Waleed Barakat.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabuk University, Tabuk, Kingdom of Saudi Arabia

    Waleed Barakat & Sherif El-Kannishy

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt

    Waleed Barakat, Ahmad Fahmy & Mohamed Askar

  3. Analytical Toxicology - Emergency Hospital, Faculty of Medicine, University of Mansoura, Mansoura, Egypt

    Sherif El-Kannishy

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  1. Waleed Barakat
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  2. Ahmad Fahmy
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Correspondence to Waleed Barakat.

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Barakat, W., Fahmy, A., Askar, M. et al. Effectiveness of arginase inhibitors against experimentally induced stroke. Naunyn-Schmiedeberg's Arch Pharmacol 391, 603–612 (2018). https://doi.org/10.1007/s00210-018-1489-1

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