Stroke is a significant public health burden which absolutely requires more effective therapies. The approved treatment options for stroke including tissue plasminogen activators, antiplatelet agents and anticoagulants mainly bear antithrombotic effects. Meanwhile, evolving investigational approaches such as collateral therapeutics and neuroprotective agents has thus far been attempted with equivocal effects on stroke outcome. The basic structural and ultrastructural changes following acute ischemic stroke should be well-considered when trying to target oxidative stress and cell death pathways using neuroprotective agents. Clearly, the positive results of preclinical studies on neuroprotectives and collateral therapeutics in stroke do not necessarily translate to the true clinical benefits of these agents. As such, several large advance-phased trials have already failed to prove so. On the other hand, controversial results in clinical setting should not discourage further research endeavors on the same. Besides, the concurrent use of flow augmentation and neuroprotectives may serve further clinical benefits. Based on the available evidence, it appears that optimization of preclinical studies and further well-designed prospective clinical trials let neuroprotection possibly find its position in stroke management. The present paper discusses key preclinical and clinical studies on neuroprotectives towards improved outcome in acute ischemic stroke.
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28-e292.
Borhani-Haghighi A, Safari R, Heydari ST, Soleimani F, Sharifian M, Yektaparast Kashkuli S, et al. Hospital mortality associated with stroke in southern iran. Iranian journal of medical sciences. 2013;38(4):314-20.
Shahtaheri RA, Borhani Haghighi A, Safari A, Cruz-Flores S. Recombinant tissue plasminogen activator (rtPA) and stroke unit for acute ischaemic stroke in developing countries, are they cost-effective? International journal of stroke : official journal of the International Stroke Society. 2012;7(7):E9.
Uflacker R, Schonholz C, Papamitisakis N, trial S. Interim report of the SENTIS trial: cerebral perfusion augmentation via partial aortic occlusion in acute ischemic stroke. The Journal of cardiovascular surgery. 2008;49(6):715-21.
Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS. Health technology assessment. 2002;6(26):1-112.
Beraki S, Litrus L, Soriano L, Monbureau M, To LK, Braithwaite SP, et al. A pharmacological screening approach for discovery of neuroprotective compounds in ischemic stroke. PloS one. 2013;8(7):e69233.
Chen J, Shehadah A, Pal A, Zacharek A, Cui X, Cui Y, et al. Neuroprotective effect of human placenta-derived cell treatment of stroke in rats. Cell transplantation. 2013;22(5):871-9.
Chieffo R, Inuggi A, Straffi L, Coppi E, Gonzalez-Rosa J, Spagnolo F, et al. Mapping early changes of cortical motor output after subcortical stroke: a transcranial magnetic stimulation study. Brain stimulation. 2013;6(3):322-9.
Peruzzotti-Jametti L, Cambiaghi M, Bacigaluppi M, Gallizioli M, Gaude E, Mari S, et al. Safety and efficacy of transcranial direct current stimulation in acute experimental ischemic stroke. Stroke; a journal of cerebral circulation. 2013;44(11):3166-74.
Hossmann KA. Pathophysiology and therapy of experimental stroke. Cellular and molecular neurobiology. 2006;26(7-8):1057-83.
Rodrigo R, Fernandez-Gajardo R, Gutierrez R, Matamala JM, Carrasco R, Miranda-Merchak A, et al. Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS & neurological disorders drug targets. 2013;12(5):698-714.
Shah K, Abbruscato T. The role of blood-brain barrier transporters in pathophysiology and pharmacotherapy of stroke. Current pharmaceutical design. 2014;20(10):1510-22.
Winship IR, Armitage GA, Ramakrishnan G, Dong B, Todd KG, Shuaib A. Augmenting collateral blood flow during ischemic stroke via transient aortic occlusion. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2014;34(1):61-71.
Yadollahikhales G, Borhani-Haghighi A, Torabi-Nami M, Edgell R, Cruz-Flores S. Flow Augmentation in Acute Ischemic Stroke. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2014.
Liebeskind DS. Collateral circulation. Stroke; a journal of cerebral circulation. 2003;34(9):2279-84.
Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke; a journal of cerebral circulation. 2007;38(3):948-54.
Bang OY, Saver JL, Kim SJ, Kim GM, Chung CS, Ovbiagele B, et al. Collateral flow predicts response to endovascular therapy for acute ischemic stroke. Stroke; a journal of cerebral circulation. 2011;42(3):693-9.
Shuaib A, Butcher K, Mohammad AA, Saqqur M, Liebeskind DS. Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target. The Lancet Neurology. 2011;10(10):909-21.
Hillis AE, Ulatowski JA, Barker PB, Torbey M, Ziai W, Beauchamp NJ, et al. A pilot randomized trial of induced blood pressure
elevation: effects on function and focal perfusion in acute and subacute stroke. Cerebrovascular diseases. 2003;16(3):236-46.
Terpolilli NA, Kim SW, Thal SC, Kataoka H, Zeisig V, Nitzsche B, et al. Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. Circulation research. 2012;110(5):727-38.
Pranevicius O, Pranevicius M, Liebeskind DS. Partial aortic occlusion and cerebral venous steal: venous effects of arterial manipulation in acute stroke. Stroke; a journal of cerebral circulation. 2011;42(5):1478-81.
Levi H, Schoknecht K, Prager O, Chassidim Y, Weissberg I, Serlin Y, et al. Stimulation of the sphenopalatine ganglion induces reperfusion and blood-brain barrier protection in the photothrombotic stroke model. PloS one. 2012;7(6):e39636.
Schellinger PD, Shuaib A, Kohrmann M, Liebeskind DS, Jovin T, Hammer MD, et al. Reduced mortality and severe disability rates in the SENTIS trial. AJNR American journal of neuroradiology. 2013;34(12):2312-6.
Shuaib A, Schwab S, Rutledge JN, Starkman S, Liebeskind DS, Bernardini GL, et al. Importance of proper patient selection and endpoint selection in evaluation of new therapies in acute stroke: further analysis of the SENTIS trial. Journal of neurointerventional surgery. 2013;5 Suppl 1:i21-4.
Leker RR, Molina C, Cockroft K, Liebeskind DS, Concha M, Shuaib A, et al. Effects of age on outcome in the SENTIS trial: better outcomes in elderly patients. Cerebrovascular diseases. 2012;34(4):263-71.
Lutsep HL, Altafullah IM, Roberts R, Silverman IE, Turco MA, Vaishnav AG. Neurologic safety event rates in the SENTIS trial control population. Acta neurologica Scandinavica. 2013;127(2):e5-7.
Hammer M, Jovin T, Wahr JA, Heiss WD. Partial occlusion of the descending aorta increases cerebral blood flow in a nonstroke porcine model. Cerebrovascular diseases. 2009;28(4):406-10.
Cortina B, Torregrosa G, Castello-Ruiz M, Burguete MC, Moscardo A, Latorre A, et al. Improvement of the circulatory function partially accounts for the neuroprotective action of the phytoestrogen genistein in experimental ischemic stroke. European journal of pharmacology. 2013;708(1-3):88-94.
De Geyter D, Stoop W, Sarre S, De Keyser J, Kooijman R. Neuroprotective efficacy of subcutaneous insulin-like growth factor-I administration in normotensive and hypertensive rats with an ischemic stroke. Neuroscience. 2013;250:253-62.
Weston RM, Lin B, Dusting GJ, Roulston CL. Targeting oxidative stress injury after ischemic stroke in conscious rats: limited benefits with apocynin highlight the need to incorporate long term recovery. Stroke research and treatment. 2013;2013:648061.
Manzanero S, Santro T, Arumugam TV. Neuronal oxidative stress in acute ischemic stroke: sources and contribution to cell injury. Neurochemistry international. 2013;62(5):712-8.
Perini F, Morra M, Alecci M, Galloni E, Marchi M, Toso V. Temporal profile of serum anti-inflammatory and pro-inflammatory interleukins in acute ischemic stroke patients. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2001;22(4):289-96.
Gu L, Wu G, Long J, Su L, Yan Y, Chen Q, et al. The role of TNF-alpha 308G>A polymorphism in the risk for ischemic stroke. The American journal of the medical sciences. 2013;345(3):227-33.
Akhtar M, Maikiyo AM, Najmi AK, Khanam R, Mujeeb M, Aqil M. Neuroprotective effects of chloroform and petroleum ether extracts of Nigella sativa seeds in stroke model of rat. Journal of pharmacy & bioallied sciences. 2013;5(2):119-25.
Bae ON, Serfozo K, Baek SH, Lee KY, Dorrance A, Rumbeiha W, et al. Safety and efficacy evaluation of carnosine, an endogenous neuroprotective agent for ischemic stroke. Stroke; a journal of cerebral circulation. 2013;44(1):205-12.
Sun L, Jin Y, Dong L, Sumi R, Jahan R, Li Z. The neuroprotective effects of Coccomyxa gloeobotrydiformis on the ischemic stroke in a rat model. International journal of biological sciences. 2013;9(8):811-7.
Dong L. QH, Zhang X., Wang C., Wang L., Cui L. Parthenolide is neuroprotective in rat experimental stroke model: downregulating NF-kappaB, phospho-p38MAPK, and caspase-1 and ameliorating BBB permeability. Mediators of inflammation. 2013:370804.
Zhang J, Fu B, Zhang X, Chen L, Zhang L, Zhao X, et al. Neuroprotective effect of bicyclol in rat ischemic stroke: down-regulates TLR4, TLR9, TRAF6, NF-kappaB, MMP-9 and up-regulates claudin-5 expression. Brain research. 2013;1528:80-8.
Yu L, Chen C, Wang LF, Kuang X, Liu K, Zhang H, et al. Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-kappaB and STAT3 in transient focal stroke. PloS one. 2013;8(2):e55839.
Godinez-Rubi M R-MA, Ortuno-Sahagun D. . Nitric oxide donors as neuroprotective agents after an ischemic stroke-related inflammatory reaction. Oxidative medicine and cellular longevity. 2013:297357.
Qi Z, Liu W, Luo Y, Ji X, Liu KJ. Normobaric hyperoxia-based neuroprotective therapies in ischemic stroke. Medical gas research. 2013;3(1):2.
Ladurner G, Kalvach P, Moessler H, Cerebrolysin Study G. Neuroprotective treatment with cerebrolysin in patients with acute stroke: a randomised controlled trial. Journal of neural transmission. 2005;112(3):415-28.
Heiss WD, Brainin M, Bornstein NM, Tuomilehto J, Hong Z, Cerebrolysin Acute Stroke Treatment in Asia I. Cerebrolysin in patients with acute ischemic stroke in Asia: results of a double-blind, placebo-controlled randomized trial. Stroke; a journal of cerebral circulation. 2012;43(3):630-6.
Ruther E, Ritter R, Apecechea M, Freytag S, Windisch M. Efficacy of the peptidergic nootropic drug cerebrolysin in patients with senile dementia of the Alzheimer type (SDAT). Pharmacopsychiatry. 1994;27(1):32-40.
Chen CL, Young SH, Gan HH, Singh R, Lao AY, Baroque AC, 2nd, et al. Chinese medicine neuroaid efficacy on stroke recovery: a double-blind, placebo-controlled, randomized study. Stroke; a journal of cerebral circulation. 2013;44(8):2093-100.
Heurteaux C, Widmann C, Moha ou Maati H, Quintard H, Gandin C, Borsotto M, et al. NeuroAiD: properties for neuroprotection and neurorepair. Cerebrovascular diseases. 2013;35 Suppl 1:1-7.
Chen CL, Venketasubramanian N, Lee CF, Wong KS, Bousser MG, Investigators CS. Effects of MLC601 on early vascular events in patients after stroke: the CHIMES study. Stroke; a journal of cerebral circulation. 2013;44(12):3580-3.
Bavarsad Shahripour R, Hemati A, Hosseinzadeh Maleki A. A randomized trial to assess the long-term safety of NeuroAiD among Caucasian patients with acute ischemic stroke. Chinese journal of integrative medicine. 2014;20(11):812-7.
Vafaee F, Zangiabadi N, Pour FM, Dehghanian F, Asadi-Shekaari M, Afshar HK. Neuroprotective effects of the immunomodulatory drug Setarud on cerebral ischemia in male rats. Neural regeneration research. 2012;7(27):2085-91.
Zhou Z, Lu T, Xu G, Yue X, Zhu W, Ma M, et al. Decreased serum brain-derived neurotrophic factor (BDNF) is associated with post-stroke depression but not with BDNF gene Val66Met polymorphism. Clinical chemistry and laboratory medicine : CCLM / FESCC. 2011;49(2):185-9.
Torabi-Nami, M., Borhani-Haghighi, A., & Vafaee, F. (2015). Neuroprotectives in Acute Ischemic Stroke, Hope or Hype?. Journal of Advanced Medical Sciences and Applied Technologies, 1(1), 8-14. doi: 10.18869/nrip.jamsat.1.1.8
Mohammad Torabi-Nami; Afshin Borhani-Haghighi; Farzaneh Vafaee. "Neuroprotectives in Acute Ischemic Stroke, Hope or Hype?". Journal of Advanced Medical Sciences and Applied Technologies, 1, 1, 2015, 8-14. doi: 10.18869/nrip.jamsat.1.1.8
Torabi-Nami, M., Borhani-Haghighi, A., Vafaee, F. (2015). 'Neuroprotectives in Acute Ischemic Stroke, Hope or Hype?', Journal of Advanced Medical Sciences and Applied Technologies, 1(1), pp. 8-14. doi: 10.18869/nrip.jamsat.1.1.8
Torabi-Nami, M., Borhani-Haghighi, A., Vafaee, F. Neuroprotectives in Acute Ischemic Stroke, Hope or Hype?. Journal of Advanced Medical Sciences and Applied Technologies, 2015; 1(1): 8-14. doi: 10.18869/nrip.jamsat.1.1.8