Preclinical studies of drugs on animal stroke models

Shmonin A.A.; Maltseva M.N.; Mel’nikova E.V.; Vlasov T.D.

doi:https://doi.org/10.17116/jnevro201711712245-52

Close metadata

Recommended articles:

Early antithrombotic protection of the brain in patients with ischemic stroke. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(8-2):5-10

Results of the implementation of reperfusion technologies in ischemic stroke. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(8-2):32-39

Results of the international multicenter randomized, double-blind, placebo-controlled clinical trial for the evaluation of the efficacy and safety of the sequential therapy with ethylmethylhydroxypyridine succinate in patients in the acute and early recovery periods of ischemic stroke (MIR). S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(8-2):40-53

Mathematical modeling of outcomes in patients with clinical combination of ischemic stroke and COVID-19 complicated by multiple organ failure. Russian Journal of Anesthesiology and Reanimatology. 2025;(3):42-49

Socio-economic damage caused by elevated low-density lipoprotein cholesterol levels. Medical Technologies. Assessment and Choice. 2025;(2):88-98

Cerebrolysin with reperfusion therapy in ischemic stroke: a prospective analysis of multimodal brain imaging data from the CEREHETIS trial. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(6):84-98

Prediction of mortality in severe ischemic stroke during COVID-19 in patients with multiorgan dysfunction. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(6):120-127

Efficacy of Recognan in the therapy of neurological disorders after traumatic brain injury. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(7):41-45

Comparative study of the neuroprotective effects of the drug Cytoflavin and citicoline in a rats model of hemorrhagic stroke. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(8):85-95

A clinical case of treating a patient with severe ischemic stroke and cancer. S.S. Korsakov Journal of Neurology and Psychiatry. 2025;(8):114-117

Abstract:

Preclinical studies are studies using experimental models of stroke in animals as well as on neurons, cell neuronal cultures and surviving brain slices. They directed both towards testing the efficacy and evaluation of the mechanisms of action of drugs, and the study of the mechanisms of ischemic damage to search for new targets for stroke treatment. This article shows the basic principles of the organization and planning of animal models of ischemic stroke. Modeling of cerebral ischemia on the different models and animal species, the modern principles of assessment of brain damage are considered as well.

Keywords:

ischemic stroke

cerebral ischemia

model of disease

preclinical research

Authors:

Shmonin A.A.

First Saint-Petersburg Pavlov State Medical University, Saint-Petersburg;
The Northwestern Federal Medical Research Center, Saint-Petersburg;
Saint-Petersburg City Hospital №26, 196247, Saint-Petersburg, Russia

Maltseva M.N.

Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia

Mel’nikova E.V.

Medical Diagnostic and Prophylactic Centre, Yaroslavl’

Vlasov T.D.

Kafedra patofiziologii

Close metadata

References:

Ginsberg MD. Current status of neuroprotection for cerebral ischemia: synoptic overview. Stroke. 2009;40(3):111-114. https://doi.org/10.1161/STROKEAHA.108.528877
Ginsberg MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology. 2008;55(3):363-389.
Labiche LA, Grotta JC. Clinical trials for cytoprotection in stroke. NeuroRx. 2004;1(1):46-70.
Majid A. Neuroprotection in stroke: past, present, and future. ISRN Neurol. 2014;21:515716. https://doi.org/10.1155/2014/515716
Baron JC, Macrae IM, Adams HP Jr, Dirnagl U. ESC-BRAIN: experimental and clinical stroke research-do they connect? Meeting report of the ESC-BRAIN joint symposium held in London and Shanghai in May 2013. Cerebrovasc Dis. 2013;36(4):306-321. https://doi.org/10.1159/000355027
O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59(3):467-477.
Philip M, Benatar M, Fisher M, Savitz SI. Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials. Stroke. 2009;40(2):577-581. https://doi.org/10.1161/STROKEAHA.108.524330
Dirnagl U, Hakim A, Macleod M, Fisher M, Howells D, Alan SM, Steinberg G, Planas A, Boltze J, Savitz S, Iadecola C, Meairs S. A concerted appeal for international cooperation in preclinical stroke research. Stroke. 2013; 44(6):1754-1760. https://doi.org/10.1161/STROKEAHA.113.000734
Sena E, van der Worp HB, Howells D, Macleod M. How can we improve the pre-clinical development of drugs for stroke? Trends Neurosci. 2007;30(9):433-439.
Shmonin AA, Baisa AE, Melnikova EV, Vavilov VN, Vlasov TD. Protective effects of early ischemic precondition in focal cerebral ischemia in rats: the role of collateral circulation. Russian Journal of Physiology I.M. Sechenov. 2011;97(2):203-213. (In Russ.)
Dirnagl U. Rodent Models of Stroke. 2010. Publisher: Humana Press; 2010.
Kahle MP, Bix GJ. Successfully Climbing the «STAIRs»: Surmounting Failed Translation of Experimental Ischemic Stroke Treatments. Stroke Res Treat. 2012;374098. https://doi.org/10.1155/2012/374098
Wang MM, Xi G, Keep RF. Should the STAIR criteria be modified for preconditioning studies? Transl Stroke Res. 2013;4(1):3-14. https://doi.org/10.1007/s12975-012-0219-0
Wang-Fischer Y. Manual of Stroke Models in Rats. USA. NY. Publisher: Taylor & Francis Group; 2009.
Chopp M, Zhang RL, Zhang ZG, Jiang Q. The clot thickens: thrombolysis and combination therapies. Acta Neurochir Suppl (Wien). 1999;73:67-71.
Zhang RL, et al. A rat model of focal embolic cerebral ischemia. Brain Res. 1997;766:83-92.
Albers GW, Goldstein LB, Hess DC, Wechsler LR, Furie KL, Gorelick PB, Hurn P, Liebeskind DS, Nogueira RG, Saver JL; STAIR VII Consortium. Stroke Treatment Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke. 2011;42(9):2645-2650. https://doi.org/10.1161/STROKEAHA.111.618850
Handbook: good laboratory practice (GLP): quality practices for regulated non-clinical research and development — 2nd ed World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases. Publisher: «WHO Library Cataloguing-in-Publication Data». 2009;327.
Mironova AN. A guide to preclinical drug research. Part one. M.: Publisher GrifiK; 2012. (In Russ.)
Chen ST, Hsu CY, Hogan EL, Maricq H, Balentine JD. A model of focal ischemic stroke in the rat: reproducible extensive cortical infarction. Stroke. 1986;17(4):738-743.
Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, Lo EH. STAIR Group. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40(6):2244-2250. https://doi.org/10.1161/STROKEAHA.108.541128
Shmonin AA, Daineko AS, Prosvirnina MS, Zukhurova M, Melnikova EV, Vlasov TD. Control of the quality of the experiment in the modeling of focal transient brain ischemia in rats using the Koidzumi technique. Regional blood circulation and microcirculation. 2014;3:74-79. (In Russ.)
Shmonin AA. Ligation of the middle cerebral artery of the rat: a comparison of modifications of models of focal cerebral ischemia in a rat. Regional blood circulation and microcirculation. 2011;3:68-76. (In Russ.)
Shmonin AA. Endogenous neuroprotection in cerebral ischemia: erythropoietin pre- and post-conditioning. Germany: Publisher «LAP LAMBERT Academic Publishing GmbH & Co»; 2012. (In Russ.)
Karkishchenko NN, Gracheva SV. A Handbook on Laboratory Animals and Alternative Models in Biomedical Research. M.: Publisher «Profil’ 2S»; 2010. (In Russ.)
McConnell VC. Calculations for the Veterinary Professional. Publisher: Ames. IA: Iowa State University Press; 2000.
Maltseva MN, Barmin AV. The effect of the content of experimental animals on certain biological indices. Materials of the international scientific conference «Biotechnologies and veterinary science. State and development prospects», February 14, 2011;88. (In Russ.)
Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol. 1985;17(5):497-504.
Shmonin AA, Baisa AE, Melnikova EV, Vavilov VN and Vlasov TD. Protective Effects of Early Ischemic Preconditioning in Focal Cerebral Ischemia in Rats: The Role of Collateral Blood Circulation. Neuroscience and Behavioral Physiology. 2012;42(6):643-650.
Graham SM, McCullough LD, Murphy SJ. Animal models of ischemic stroke: balancing experimental aims and animal care. Comp Med. 2004;54(5):486-496.
Traystman RJ. Animal models of focal and global cerebral ischemia. ILAR J. 2003;44(2):85-95.
Shmonin AA, Melnikova EV, Galagudza MM, Vlasov TD. The characteristics of cerebral ischemia in major rat stroke models of middle cerebral artery ligation through craniectomy. International Journal of Stroke. 2014;9(6):793-801. https://doi.org/10.1111/j.1747-4949.2012.00947.x
Koizumi J, Yoshida Y, Nakazawa T, Ooneda G. 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. 1986;8:1-8.
Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20:84-91.
Korzhevsky DE, Kirik OV, Baisa AE, Vlasov TD. Simulation of unilateral ischemic injury of striatum neurons with the help of a short occlusion of the middle cerebral artery. Bulletin of Experimental Biology and Medicine. 2009;147(2):217-219. (In Russ.)
Korzhevsky DE, Kirik OV, Sukhorukova EG, Vlasov TD. Structural organization of striatum microgliocytes after transient focal ischemia, Morphology. 2012;141(2):28-32. (In Russ.)
Sundt TM Jr, Waltz AG. Experimental cerebral infarction: Retro-orbital extradural approach for occluding the middle cerebral artery. Mayo Clin Proc. 1966;41(3):159-168.
Polyakova EA, Dranishnikov NV, Vlasov TD. A method for modeling reversible occlusion of the middle cerebral artery. Regional blood circulation and microcirculation. 2004;3:61-63. (In Russ.)
Windle V, Szymanska A, Granter-Button S, White C, Buist R, Peeling J, Corbett D. An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat. Exp Neurol. 2006;201(2):324-334.
Telpukhov VI, Terenin SO, Knyazeva GD, Lapkina TI. Prolongation of safe periods of cerebral ischemia. Bulletin of the Academy of Medical Sciences. 1985;4:65-71. (In Russ.)
Perez-Pinzon MA, Guang-Ping X, Dietrich VD and all. Rapid preconditioning protects rats against ischemic neuronal damage after 3 but not 7 days of reperfusion following global cerebral ischemia. J of Cerebral Blood Flow and Metabolism. 1997;17:175-182.
Zhao L, Nowak TS Jr. CBF changes associated with focal ischemic preconditioning in the spontaneously hypertensive rat. J Cereb Blood Flow Metab. 2006;26(9):1128-1140.
Tsygan NV. Damage and protection of the brain during cardiac surgery in conditions of artificial circulation (experimental clinical study) [dissertation]. SPb. 2014. (In Russ.) http://medical-diss.com/docreader/514714/d#?page=10
Shcherbak NS, Galagudza MM. Experimental models of ischemic stroke. Bulletin of the FCSKE them V.A. Almazova. 2011;3:39-47. (In Russ.)
Shcherbak NS, Galagudza MM, Ovchinnikov DA, Kuzmenkov AN, Mitrofanova LB, Barantsevich ER, Shlyakhto EV. A new way of modeling reversible global cerebral ischemia in rats. Bulletin of Experimental Biology and Medicine. 2011;152(11):592-595. (In Russ.)
Bilenko MV. Ischemic and reperfusion injury of organs. М.: Medicine; 1989. (In Russ.)
Chen J, Simon R. Ischemic tolerance in the brain. J Neurology. 1997;48(2): 306-311.
Korbachev VG, Sisenkov S.P. Modeling of clinical death and postresuscitation disease in rats. Pathological physiology and experimental therapy. 1982;3:78-80. (In Russ.)
Zhang RL, Zhang ZG, Lu M, Wang Y, Yang JJ, Chopp M. Reduction of the cell cycle length by decreasing G1 phase and cell cycle reentry expand neuronal progenitor cells in the subventricular zone of adult rat after stroke. J Cereb Blood Flow Metab. 2006;26(6):857-863.
Zakharov YuM. Non-erythropoietic properties of erythropoietin. Russian Physiological Journal. I.S. Sechenova. 2007:93(6):592-608. (In Russ.)
Noguchi CT, Asavaritikrai P, Teng R, Jia Y. Role of erythropoietin in the brain. Crit Rev Oncol Hematol. 2007;64(2):159-171.
Canazza A, Minati L, Boffano C, Parati E, Binks S. Experimental models of brain ischemia: a review of techniques, magnetic resonance imaging, and investigational cell-based therapies. Front Neurol. 2014;19(5):19. https://doi.org/10.3389/fneur.2014.00019
Daineko AS, Shmonin AA, Shumeeva AG, Kovalenko EA, Melnikova EV, Vlasov TD. Assess mentof neurological deficitinthe early and late phase after a 30-minute of focal cerebral ischemia in rats. Regional blood circulation and microcirculation. 2014;13(1):49:68-78. (In Russ.)
Minnerup J, Wersching H, Diederich K, Schilling M, Ringelstein EB, Wellmann J, Schäbitz WR. Methodological quality of preclinical stroke studies is not required for publication in high-impact journals. J Cereb Blood Flow Metab. 2010;30(9):1619-1624. https://doi.org/10.1038/jcbfm.2010.74
van der Worp HB, de Haan P, Morrema E, Kalkman CJ. Methodological quality of animal studies on neuroprotection in focal cerebral ischemia. J Neurol. 2005;252(9):1108-1114.