The Open Biology Journal




ISSN: 1874-1967 ― Volume 7, 2019
REVIEW ARTICLE

Overview of Advances in the Pathophysiology and Treatment of Stroke: A New Plan for Stroke Treatment



Hamidreza Famitafreshi1, Morteza Karimian1, *
1 Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Despite many advances in the treatment of stroke, this disease still causes great morbidity and mortality. For this purpose, different kinds of studies have been conducted based on different mechanisms. The research findings highlight the role of remote ischemic preconditioning, microRNAs, neurogenesis, inflammation, and oxidative stress. Nearly a quarter of patients with ischemic stroke will experience a recurrent stroke. It means not just immediate intervention, but also long term intervention is necessary to alleviate stroke patients. Therefore, it is mandatory to predict unwanted events and implement a thoughtful treatment, especially targeting high-risk patients with a high rate of mortality and morbidity. In this review, new advances in animal models have been proposed and overall, it is concluded that stroke patients may greatly benefit from multidisciplinary solutions and more studies are being conducted for timely implementing the best therapy.

Keywords: Stroke, Remote ischemic conditioning, MicroRNA, Neurogenesis, Inflammation, Pathophysiology.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 7
First Page: 39
Last Page: 44
Publisher Id: TOBIOJ-7-39
DOI: 10.2174/1874196701907010039

Article History:

Received Date: 10/09/2019
Revision Received Date: 22/10/2019
Acceptance Date: 29/10/2019
Electronic publication date: 28/11/2019
Collection year: 2019

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© 2019 Famitafreshi and Karimian

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Physiology, Tehran University of Medical Sciences, Tehran, Iran; Tel: +982166419484;
E-mail: karimian@tums.ac.ir






1. INTRODUCTION

Despite many advances in the treatment of stroke and its sequels [1Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet 2011; 377(9778): 1693-702.
[http://dx.doi.org/10.1016/S0140-6736(11)60325-5] [PMID: 21571152]
, 2Laver KE, Lange B, George S, Deutsch JE, Saposnik G, Crotty M. Virtual reality for stroke rehabilitation. Cochrane database of systematic reviews 2017; (11): CD008349.
[http://dx.doi.org/10.1002/14651858.CD008349.pub4]
], stroke is still the main disease that has the greatest burden of mortality and morbidity [3Ingall T. Stroke--incidence, mortality, morbidity and risk. J Insur Med 2004; 36(2): 143-52.
[PMID: 15301227]
, 4Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update a report from the American Heart Association. Circulation 2016; 133(4): e38-e360.
[PMID: 26673558]
]. It is obvious that by increasing the global population of people who suffer ischemic episodes, the more people would suffer from this severe disease [5Mukherjee D, Patil CG. Epidemiology and the global burden of stroke. World Neurosurg 2011; 76(6)(Suppl.): S85-90.
[http://dx.doi.org/10.1016/j.wneu.2011.07.023] [PMID: 22182277]
-7Di Carlo A. Human and economic burden of stroke 2009.]. People who are older than 65 years of age are the population that is at great risk of morbidity and mortality, and also overall, the incidence of stroke has been increased [8Pan A, Sun Q, Okereke OI, Rexrode KM, Hu FB. Depression and risk of stroke morbidity and mortality: A meta-analysis and systematic review. JAMA 2011; 306(11): 1241-9.
[http://dx.doi.org/10.1001/jama.2011.1282] [PMID: 21934057]
-10Katan M, Luft A, Eds. EdsGlobal burden of stroke Seminars in neurology 2018; 38(2): 208-11.]. However, it would not be surprising to see this disease in younger people. Considering the global burden of the disease, many studies have been conducted to reduce the morbidity and mortality from this serious disease [11Schrader J, Lüders S, Kulschewski A, et al. Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke 2005; 36(6): 1218-26.
[http://dx.doi.org/10.1161/01.STR.0000166048.35740.a9] [PMID: 15879332]
, 12Brewer L, Horgan F, Hickey A, Williams D. Stroke rehabilitation: recent advances and future therapies. QJM 2013; 106(1): 11-25.
[http://dx.doi.org/10.1093/qjmed/hcs174] [PMID: 23019591]
]. New strategies and treatments have been conducted for the prevention, immediate and long-term treatment of stroke [13Rothwell PM, Algra A, Amarenco P. Medical treatment in acute and long-term secondary prevention after transient ischaemic attack and ischaemic stroke. Lancet 2011; 377(9778): 1681-92.
[http://dx.doi.org/10.1016/S0140-6736(11)60516-3] [PMID: 21571151]
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[http://dx.doi.org/10.1160/TH14-03-0231] [PMID: 24687081]
]. Here, new advances in managing this disease and its complications, especially in animal models have been discussed.

2. DISCUSSION

2.1. Remote Ischemic Conditioning as a Protective Treatment

The protective role of oxygen deprivation was known in 1939 [16Baranova K. Remote ischemic conditioning of the brain: Phenomena and mechanisms. Neurochem J 2017; 11(3): 189-93.
[http://dx.doi.org/10.1134/S1819712417030023]
]. However, in 80s, new experiments were performed to investigate this protective phenomenon [17Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74(5): 1124-36.
[http://dx.doi.org/10.1161/01.CIR.74.5.1124] [PMID: 3769170]
]. Many studies were performed to investigate the protective effect of Remote Ischemic preconditioning (RIC). The protective role of RIC is limited only to the brain, but also RIC has a protective role in other organs such as lung, liver, and skin [18Candilio L, Malik A, Hausenloy DJ. Protection of organs other than the heart by remote ischemic conditioning. J Cardiovasc Med (Hagerstown) 2013; 14(3): 193-205.
[http://dx.doi.org/10.2459/JCM.0b013e328359dd7b] [PMID: 23079610]
]. In addition, many other diseases such as renal disease will benefit from RIC [19Zarbock A, Schmidt C, Van Aken H, et al. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: A randomized clinical trial. JAMA 2015; 313(21): 2133-41.
[http://dx.doi.org/10.1001/jama.2015.4189] [PMID: 26024502]
]. For sure, RIC would activate adaptive mechanisms in neurons, but the exact mechanism for its protective role has not fully understood. However, hypoxia-inducible factor 1 recently has been proposed to be necessary for the protective role of RIC [20Cai Z, Luo W, Zhan H, Semenza GL. Hypoxia-inducible factor 1 is required for remote ischemic preconditioning of the heart. Proc Natl Acad Sci USA 2013; 110(43): 17462-7.
[http://dx.doi.org/10.1073/pnas.1317158110] [PMID: 24101519]
]. Macrophage activation has also been considered as a key event in the progression of reperfusion injury which is known as the source of extracellular Reactive Oxygen Species (ROS) [21Taguchi A, Soma T, Tanaka H, et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest 2004; 114(3): 330-8.
[http://dx.doi.org/10.1172/JCI200420622] [PMID: 15286799]
]. Meanwhile, there is a window period that the ischemic myocardia can be secured before necrosis established. In this regard, activation of neutrophils, adhesion molecules and cytokine release are necessary for the induction of necrosis, but RIC yet has not been shown to influence these mechanisms. RIC is not just useful for stoke as the consequence of atheroma plaque but also in different conditions, it is an effective strategy. RIC treatment prevents stroke in intracranial arterial stenosis [22Meng R, Asmaro K, Meng L, et al. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 2012; 79(18): 1853-61.
[http://dx.doi.org/10.1212/WNL.0b013e318271f76a] [PMID: 23035060]
], focal ischemia [23Ren C, Yan Z, Wei D, Gao X, Chen X, Zhao H. Limb remote ischemic postconditioning protects against focal ischemia in rats. Brain Res 2009; 1288: 88-94.
[http://dx.doi.org/10.1016/j.brainres.2009.07.029] [PMID: 19631625]
] and after subarachnoid hemorrhage [24Koch S, Katsnelson M, Dong C, Perez-Pinzon M. Remote ischemic limb preconditioning after subarachnoid hemorrhage: A phase Ib study of safety and feasibility. Stroke 2011; 42(5): 1387-91.
[http://dx.doi.org/10.1161/STROKEAHA.110.605840] [PMID: 21415404]
]. RIC can also be induced by chronic peripheral hypoperfusion, not just by occlusion of vessels [25Connolly M, Bilgin-Freiert A, Ellingson B, et al. Peripheral vascular disease as remote ischemic preconditioning, for acute stroke. Clin Neurol Neurosurg 2013; 115(10): 2124-9.
[http://dx.doi.org/10.1016/j.clineuro.2013.07.038] [PMID: 23958050]
]. Stroke as the side-effect of cardiovascular surgeries and intervention of palliative care in the cardiovascular system can be alleviated by RIC [26Hausenloy DJ, Candilio L, Evans R, et al. Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 2015; 373(15): 1408-17.
[http://dx.doi.org/10.1056/NEJMoa1413534] [PMID: 26436207]
-28Thielmann M, Kottenberg E, Boengler K, et al. Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res Cardiol 2010; 105(5): 657-64.
[http://dx.doi.org/10.1007/s00395-010-0104-5] [PMID: 20495811]
].

2.2. Role of microRNAs in Determining the Outcome of Stroke

MicroRNAs are small, non-coding RNAs that, in recent years, have got very much attention for the treatment of stroke [29Zeng Y, Liu JX, Yan ZP, Yao XH, Liu XH. Potential microRNA biomarkers for acute ischemic stroke. Int J Mol Med 2015; 36(6): 1639-47.
[http://dx.doi.org/10.3892/ijmm.2015.2367] [PMID: 26459744]
-35Li S-H, Su S-Y, Liu J-L. Differential regulation of microRNAs in patients with ischemic stroke. Curr Neurovasc Res 2015; 12(3): 214-21.
[http://dx.doi.org/10.2174/1567202612666150605121709] [PMID: 26044809]
]. MicroRNAs have a role in many neuronal processes such as development, differentiation, synaptic plasticity [36Cohen JE, Lee PR, Chen S, Li W, Fields RD. MicroRNA regulation of homeostatic synaptic plasticity. Proc Natl Acad Sci USA 2011; 108(28): 11650-5.
[http://dx.doi.org/10.1073/pnas.1017576108] [PMID: 21697510]
], apoptosis [37Wang Y, Lee CG. MicroRNA and cancer--focus on apoptosis. J Cell Mol Med 2009; 13(1): 12-23.
[http://dx.doi.org/10.1111/j.1582-4934.2008.00510.x] [PMID: 19175697]
] and neurodegeneration [38Bushati N, Cohen SM. MicroRNAs in neurodegeneration. Curr Opin Neurobiol 2008; 18(3): 292-6.
[http://dx.doi.org/10.1016/j.conb.2008.07.001] [PMID: 18662781]
]. It has been shown that microRNAs can influence the outcome of stroke. Some microRNAs improve and some microRNAs deteriorate the process of stroke [39Khoshnam SE, Winlow W, Farbood Y, Moghaddam HF, Farzaneh M. Emerging roles of microRNAs in ischemic stroke: As possible therapeutic agents. J Stroke 2017; 19(2): 166-87.
[http://dx.doi.org/10.5853/jos.2016.01368] [PMID: 28480877]
]. MicroRNAs in the pathogenesis of atheroma plaque, stroke, and its complications have a more validated role compared to RIC. They are present in atherosclerosis, hyperlipidemia, hypertension and plaque rupture [40Rink C, Khanna S. MicroRNA in ischemic stroke etiology and pathology. Physiol Genomics 2011; 43(10): 521-8.
[http://dx.doi.org/10.1152/physiolgenomics.00158.2010] [PMID: 20841499]
]. Following ischemia, a profound change in microRNA transcriptome occurs in the myocardium [41Dharap A, Bowen K, Place R, Li L-C, Vemuganti R. Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab 2009; 29(4): 675-87.
[http://dx.doi.org/10.1038/jcbfm.2008.157] [PMID: 19142192]
-43Liu D-Z, Tian Y, Ander BP, et al. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab 2010; 30(1): 92-101.
[http://dx.doi.org/10.1038/jcbfm.2009.186] [PMID: 19724284]
]. Apart from other microRNAs that are release after ischemia, two microRNAs are pathophysiologically active in the window period. These are microRNA-15a and microRNA 497. These two microRNAs have a negative role in the pathophysiology of stroke. They impair the normal defense mechanism that begins after ischemia present inside the cells. MicroRNA-15a inhibits expression of Bcl-2 [44Yin K-J, Deng Z, Hamblin M, et al. Peroxisome proliferator-activated receptor δ regulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. J Neurosci 2010; 30(18): 6398-408.
[http://dx.doi.org/10.1523/JNEUROSCI.0780-10.2010] [PMID: 20445066]
] and microRNA 497 interferes with the normal function of Bcl-2 [45Yin K-J, Deng Z, Huang H, et al. miR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia. Neurobiol Dis 2010; 38(1): 17-26.
[http://dx.doi.org/10.1016/j.nbd.2009.12.021] [PMID: 20053374]
] that has an antiapoptotic role. Further studies suggest that reduction of the production of such microRNAs protects the blood-brain barrier (BBB). RIC treatment has been shown to cause up-regulation of the member of microRNA 200 family (200 a, 200 b and 429) [46Lee S-T, Chu K, Jung K-H, et al. MicroRNAs induced during ischemic preconditioning. Stroke 2010; 41(8): 1646-51.
[http://dx.doi.org/10.1161/STROKEAHA.110.579649] [PMID: 20576953]
]. About the effectiveness of microRNA directed therapy for the alleviation of stroke, further studies should be done to validate the specific treatment. However, microRNA-targeted therapy that promotes cell survival can be considered in this regard [47Hellings WE, Peeters W, Moll FL, Pasterkamp G. From vulnerable plaque to vulnerable patient: The search for biomarkers of plaque destabilization. Trends Cardiovasc Med 2007; 17(5): 162-71.
[http://dx.doi.org/10.1016/j.tcm.2007.03.006] [PMID: 17574124]
]. In a recent study, microRNA, Let7f has been successfully used for neuroprotection in ischemic stroke model [48Selvamani A, Sathyan P, Miranda RC, Sohrabji F. An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model. PLoS One 2012; 7(2)e32662
[http://dx.doi.org/10.1371/journal.pone.0032662] [PMID: 22393433]
]. MicroRNA 124a in the subventricular zone [49Liu XS, Chopp M, Zhang RL, et al. MicroRNA profiling in subventricular zone after stroke: MiR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway. PLoS One 2011; 6(8)e23461
[http://dx.doi.org/10.1371/journal.pone.0023461] [PMID: 21887253]
] and microRNA 17-92 [50Liu XS, Chopp M, Wang XL, et al. MicroRNA-17-92 cluster mediates the proliferation and survival of neural progenitor cells after stroke. J Biol Chem 2013; 288(18): 12478-88.
[http://dx.doi.org/10.1074/jbc.M112.449025] [PMID: 23511639]
] have also been successfully used in the stroke model through increased survival of ischemic cells. MicroRNA 107 contributes to post-stroke angiogenesis [31Li Y, Mao L, Gao Y, Baral S, Zhou Y, Hu B. MicroRNA-107 contributes to post-stroke angiogenesis by targeting Dicer-1. Sci Rep 2015; 5: 13316.
[http://dx.doi.org/10.1038/srep13316] [PMID: 26294080]
]. Targeting other cells such as oligodendrocytes that may help better healing of ischemic region is also a useful treatment. MicroRNA 146a promotes oligodendrocytes in the ischemic region [51Liu XS, Chopp M, Pan WL, et al. MicroRNA-146a promotes oligodendrogenesis in stroke. Mol Neurobiol 2017; 54(1): 227-37.
[http://dx.doi.org/10.1007/s12035-015-9655-7] [PMID: 26738853]
].

2.3. Neurogenesis, Angiogenesis, and Synaptogenesis

The generation of new neurons after birth in certain brain regions is called Neurogenesis [52Ming GL, Song H. Adult neurogenesis in the mammalian brain: Significant answers and significant questions. Neuron 2011; 70(4): 687-702.
[http://dx.doi.org/10.1016/j.neuron.2011.05.001] [PMID: 21609825]
]. In mammals, in some brain areas, continuous neuron production is well documented: the Subventricular Zone of the lateral ventricle (SVZ) and the dentate gyrus of the hippocampus [53Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965; 124(3): 319-35.
[http://dx.doi.org/10.1002/cne.901240303] [PMID: 5861717]
]. From the SVZ, neuronal progenitors migrate along the Rostral Migratory Stream (RMS) into the Olfactory Bulb (OB), where they differentiate into granule and periglomerular neurons [54Lois C, Alvarez-Buylla A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci USA 1993; 90(5): 2074-7.
[http://dx.doi.org/10.1073/pnas.90.5.2074] [PMID: 8446631]
-56Luskin MB. Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 1993; 11(1): 173-89.
[http://dx.doi.org/10.1016/0896-6273(93)90281-U] [PMID: 8338665]
]. In contrast, glial progenitor cells migrate radially into neighboring brain structures such as the striatum, corpus callosum, and neocortex [57Levison SW, Goldman JE. Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain. Neuron 1993; 10(2): 201-12.
[http://dx.doi.org/10.1016/0896-6273(93)90311-E] [PMID: 8439409]
, 58Levison SW, Chuang C, Abramson BJ, Goldman JE. The migrational patterns and developmental fates of glial precursors in the rat subventricular zone are temporally regulated. Development 1993; 119(3): 611-22.
[PMID: 8187632]
]. The migration of new neurons for neurogenesis niche specifically the subventricular zone, may improve the outcome of stroke [59Ohab JJ, Fleming S, Blesch A, Carmichael ST. A neurovascular niche for neurogenesis after stroke. J Neurosci 2006; 26(50): 13007-16.
[http://dx.doi.org/10.1523/JNEUROSCI.4323-06.2006] [PMID: 17167090]
]. In the recent two decades, many studies have been conducted to investigate the effectiveness of this new phenomena (Neurogenesis) in brain diseases such as stroke and these studies suggest that this self-impair capacity alone fails to reconstruct the infarcted area after stroke and there should be some regulators for healing of the infarcted area that increases the efficacy of newly generated neurons [60Lie DC, Song H, Colamarino SA, Ming GL, Gage FH. Neurogenesis in the adult brain: New strategies for central nervous system diseases. Annu Rev Pharmacol Toxicol 2004; 44: 399-421.
[http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121631] [PMID: 14744252]
, 61Baldauf K, Reymann KG. Influence of EGF/bFGF treatment on proliferation, early neurogenesis and infarct volume after transient focal ischemia. Brain Res 2005; 1056(2): 158-67.
[http://dx.doi.org/10.1016/j.brainres.2005.07.035] [PMID: 16125154]
]. Studies in this regard suggest that some agents such as Epithelial Growth Factor and basic Fibroblast Growth Factor (EGF/bFGF) and Transforming Growth Factor α (TGFα) may increase the efficacy of recruited neurons for reduction of infarct volume [61Baldauf K, Reymann KG. Influence of EGF/bFGF treatment on proliferation, early neurogenesis and infarct volume after transient focal ischemia. Brain Res 2005; 1056(2): 158-67.
[http://dx.doi.org/10.1016/j.brainres.2005.07.035] [PMID: 16125154]
-63Ma M, Ma Y, Yi X, et al. Intranasal delivery of transforming growth factor-beta1 in mice after stroke reduces infarct volume and increases neurogenesis in the subventricular zone. BMC Neurosci 2008; 9(1): 117.
[http://dx.doi.org/10.1186/1471-2202-9-117] [PMID: 19077183]
]. It should be remembered that the recruited new neurons themselves may be sufficient for exerting such a healing effect. Neurogenesis in other brain areas such as forebrain [64Kernie SG, Parent JM. Forebrain neurogenesis after focal Ischemic and traumatic brain injury. Neurobiol Dis 2010; 37(2): 267-74.
[http://dx.doi.org/10.1016/j.nbd.2009.11.002] [PMID: 19909815]
], cortical areas [65Gu W, Brännström T, Wester P. Cortical neurogenesis in adult rats after reversible photothrombotic stroke. J Cereb Blood Flow Metab 2000; 20(8): 1166-73.
[http://dx.doi.org/10.1097/00004647-200008000-00002] [PMID: 10950377]
], hippocampus [66Li WL, Cai HH, Wang B, et al. Chronic fluoxetine treatment improves ischemia-induced spatial cognitive deficits through increasing hippocampal neurogenesis after stroke. J Neurosci Res 2009; 87(1): 112-22.
[http://dx.doi.org/10.1002/jnr.21829] [PMID: 18711744]
] and striatum [67Parent JM, Vexler ZS, Gong C, Derugin N, Ferriero DM. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 2002; 52(6): 802-13.
[http://dx.doi.org/10.1002/ana.10393] [PMID: 12447935]
] has been observed following a stroke. This phenomenon encouraged new studies that are directed at knowing the exact mechanism of this recruitment and also proposing effective treatment on this basis. Later studies proposed that the application of some drugs by improving neurogenesis improves the outcome of stroke. Drugs such as valproic acid [68Liu XS, Chopp M, Kassis H, et al. Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience 2012; 220: 313-21.
[http://dx.doi.org/10.1016/j.neuroscience.2012.06.012] [PMID: 22704966]
], erythropoietin [69Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 2004; 35(7): 1732-7.
[http://dx.doi.org/10.1161/01.STR.0000132196.49028.a4] [PMID: 15178821]
], statins [70Chen J, Zhang ZG, Li Y, et al. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 2003; 53(6): 743-51.
[http://dx.doi.org/10.1002/ana.10555] [PMID: 12783420]
], sildenafil [71Zhang R, Wang Y, Zhang L, et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 2002; 33(11): 2675-80.
[http://dx.doi.org/10.1161/01.STR.0000034399.95249.59] [PMID: 12411660]
], transforming growth factor α [72Leker RR, Toth ZE, Shahar T, et al. Transforming growth factor α induces angiogenesis and neurogenesis following stroke. Neuroscience 2009; 163(1): 233-43.
[http://dx.doi.org/10.1016/j.neuroscience.2009.05.050] [PMID: 19481589]
], retinoic acid [73Plane JM, Whitney JT, Schallert T, Parent JM. Retinoic acid and environmental enrichment alter subventricular zone and striatal neurogenesis after stroke. Exp Neurol 2008; 214(1): 125-34.
[http://dx.doi.org/10.1016/j.expneurol.2008.08.006] [PMID: 18778705]
], N-methyl-D-aspartate mediated therapy [74Arvidsson A, Kokaia Z, Lindvall O. N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur J Neurosci 2001; 14(1): 10-8.
[http://dx.doi.org/10.1046/j.0953-816x.2001.01611.x] [PMID: 11488944]
], nitric oxide donor [75Zhang R, Zhang L, Zhang Z, et al. A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats. Ann Neurol 2001; 50(5): 602-11.
[http://dx.doi.org/10.1002/ana.1249] [PMID: 11706966]
], omega-3 polyunsaturated fatty acids [76Hu X, Zhang F, Leak RK, et al. Transgenic overproduction of omega-3 polyunsaturated fatty acids provides neuroprotection and enhances endogenous neurogenesis after stroke. Curr Mol Med 2013; 13(9): 1465-73.
[http://dx.doi.org/10.2174/15665240113139990075] [PMID: 23971733]
], cerebrolysin [77Zhang C, Chopp M, Cui Y, et al. Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. J Neurosci Res 2010; 88(15): 3275-81.
[http://dx.doi.org/10.1002/jnr.22495] [PMID: 20857512]
], administration of CD34+, fluoxetine [66Li WL, Cai HH, Wang B, et al. Chronic fluoxetine treatment improves ischemia-induced spatial cognitive deficits through increasing hippocampal neurogenesis after stroke. J Neurosci Res 2009; 87(1): 112-22.
[http://dx.doi.org/10.1002/jnr.21829] [PMID: 18711744]
]and exercise [78Luo CX, Jiang J, Zhou QG, et al. Voluntary exercise-induced neurogenesis in the postischemic dentate gyrus is associated with spatial memory recovery from stroke. J Neurosci Res 2007; 85(8): 1637-46.
[http://dx.doi.org/10.1002/jnr.21317] [PMID: 17465031]
] are included.

2.4. Inflammation Process

Inflammation is a complex process that encompasses the accumulation of immune cells in a certain region [79Scott A, Khan KM, Cook JL, Duronio V. What is “inflammation”? Are we ready to move beyond Celsus? Br J Sports Med 2004; 38(3): 248-9.
[http://dx.doi.org/10.1136/bjsm.2003.011221] [PMID: 15155418]
]. During this complex process, certain receptors will appear in immune cells and also certain mediators will be released [80Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: Signals in resolution. Nat Immunol 2001; 2(7): 612-9.
[http://dx.doi.org/10.1038/89759] [PMID: 11429545]
]. It has been shown that after stroke, certain inflammatory processes will occur in the ischemic region [81Clark RK, Lee EV, White RF, Jonak ZL, Feuerstein GZ, Barone FC. Reperfusion following focal stroke hastens inflammation and resolution of ischemic injured tissue. Brain Res Bull 1994; 35(4): 387-92.
[http://dx.doi.org/10.1016/0361-9230(94)90119-8] [PMID: 7850491]
]. Various kinds of immune cells recruited to the ischemic region including Microglial cells, neutrophils, macrophages/monocytes and T-cells [80Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: Signals in resolution. Nat Immunol 2001; 2(7): 612-9.
[http://dx.doi.org/10.1038/89759] [PMID: 11429545]
]. Modulation of the immune system will decrease the size of infarct [21Taguchi A, Soma T, Tanaka H, et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. J Clin Invest 2004; 114(3): 330-8.
[http://dx.doi.org/10.1172/JCI200420622] [PMID: 15286799]
, 82Hurn PD, Subramanian S, Parker SM, et al. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J Cereb Blood Flow Metab 2007; 27(11): 1798-805.
[http://dx.doi.org/10.1038/sj.jcbfm.9600482] [PMID: 17392692]
, 83Ormstad H, Aass HCD, Lund-Sørensen N, Amthor K-F, Sandvik L. Serum levels of cytokines and C-reactive protein in acute ischemic stroke patients, and their relationship to stroke lateralization, type, and infarct volume. J Neurol 2011; 258(4): 677-85.
[http://dx.doi.org/10.1007/s00415-011-6006-0] [PMID: 21424610]
]. Post-ischemic inflammation leads to dysfunction of the blood-brain barrier, cerebral edema, and neuronal cell death [84Lakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: Therapeutic approaches. J Transl Med 2009; 7(1): 97.
[http://dx.doi.org/10.1186/1479-5876-7-97] [PMID: 19919699]
]. The important question in this regard is the old concept about the brain that has been thought to be an immune-privileged organ. Microglial cells are thought to be the immune modulator during the stroke. The number of microglial cells increases after stroke in the infarcted area [85Ekdahl CT, Kokaia Z, Lindvall O. Brain inflammation and adult neurogenesis: The dual role of microglia. Neuroscience 2009; 158(3): 1021-9.
[http://dx.doi.org/10.1016/j.neuroscience.2008.06.052] [PMID: 18662748]
]. In fact, microglial cells can play two distinct roles: protective effect and destructive effect. The protective role is the result of the production of neurotrophic substances Brain-derived Neurotrophic Factor (BDNF), insulin-like growth factor I (IGF-I), and several other growth factors. The destructive effects mainly mediated by releasing several pro-inflammatory cytokines such as TNF-α, interleukin-1β (IL-1β), and IL-6, as well as other potential cytotoxic molecules including Nitric Oxide (NO), ROS, and prostanoids [86Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol 2006; 147(S1)(Suppl. 1): S232-40.
[http://dx.doi.org/10.1038/sj.bjp.0706400] [PMID: 16402109]
]. Microglial cells by the production of proinflammatory cytokines can trigger the emergence of adhesion molecules and, therefore recruitment of inflammatory cells to penumbras. In this sense, a new therapy has been proposed for the reduction of inflammation in the infarcted area [87Veldhuis WB, Derksen JW, Floris S, et al. Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat. J Cereb Blood Flow Metab 2003; 23(9): 1029-39.
[http://dx.doi.org/10.1097/01.WCB.0000080703.47016.B6] [PMID: 12973019]
, 88Bodhankar S, Chen Y, Vandenbark AA, Murphy SJ, Offner H. IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke. Metab Brain Dis 2013; 28(3): 375-86.
[http://dx.doi.org/10.1007/s11011-013-9413-3] [PMID: 23640015]
]. Based on this observation, inflammatory mediators and cells can be used to assess the outcome of stroke. In one study, IL-6 has been used to assess the severity of stroke [89Smith CJ, Emsley HC, Gavin CM, et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004; 4(1): 2.
[http://dx.doi.org/10.1186/1471-2377-4-2] [PMID: 14725719]
] and Toll-like receptor 4 has been considered as the marker that is associated with severe stroke [90Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 2007; 115(12): 1599-608.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.603431] [PMID: 17372179]
]. Regulatory T cells have a protective role during the stroke [91Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 2009; 15(2): 192-9.
[http://dx.doi.org/10.1038/nm.1927] [PMID: 19169263]
]. Metalloproteinase, based on its anti-inflammatory properties, has been proposed for the treatment of stroke [92Morancho A, Rosell A, García-Bonilla L, Montaner J. Metalloproteinase and stroke infarct size: Role for anti-inflammatory treatment? Ann N Y Acad Sci 2010; 1207(1): 123-33.
[http://dx.doi.org/10.1111/j.1749-6632.2010.05734.x] [PMID: 20955435]
].

2.5. Oxidative Stress (OS)

The balance of oxidative stress is a detrimental factor for normal body function, including the brain [93Floyd RA, Carney JM. Free radical damage to protein and DNA: Mechanisms involved and relevant observations on brain undergoing oxidative stress. Ann Neurol 1992; 32(S1)(Suppl.): S22-7.
[http://dx.doi.org/10.1002/ana.410320706] [PMID: 1510377]
]. It has been shown that during acute ischemia, considerable oxidative stress is present in the region of ischemia [94Vignini A. Stroke and oxidative stress Oxidative stress and free radical damage in neurology 2011; 137-52.
[http://dx.doi.org/10.1007/978-1-60327-514-9_9]
]. In this sense, oxidative stress during ischemia is the cause of great mortality [94Vignini A. Stroke and oxidative stress Oxidative stress and free radical damage in neurology 2011; 137-52.
[http://dx.doi.org/10.1007/978-1-60327-514-9_9]
]. It is proposed that during the ischemic period, rapid reperfusion causes the second period of reactive oxygen species (ROS) generation that causes more damages, such as disruption of the Blood-brain Barrier (BBB) [53Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965; 124(3): 319-35.
[http://dx.doi.org/10.1002/cne.901240303] [PMID: 5861717]
, 95Cherubini A, Ruggiero C, Polidori MC, Mecocci P. Potential markers of oxidative stress in stroke. Free Radic Biol Med 2005; 39(7): 841-52.
[http://dx.doi.org/10.1016/j.freeradbiomed.2005.06.025] [PMID: 16140205]
]. The resultant ROS generation will affect the outcome of stroke. ROS causes autophagy, apoptosis, and necrosis [96Golstein P, Kroemer G. Cell death by necrosis: Towards a molecular definition. Trends Biochem Sci 2007; 32(1): 37-43.
[http://dx.doi.org/10.1016/j.tibs.2006.11.001] [PMID: 17141506]
, 97Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N. Crosstalk between apoptosis, necrosis and autophagy. Biochimica et Biophysica Acta (BBA)-. Molecular Cell Research 2013; 1833(12): 3448-59.]. The beneficial effects of antioxidant therapy are evolved from animal studies. It has been shown that vitamin C and E therapy along with other antioxidant agents such as NADPH-oxidase and Flavanol, will improve the outcome of stroke [98Chen X, Touyz RM, Park JB, Schiffrin EL. Antioxidant effects of vitamins C and E are associated with altered activation of vascular NADPH oxidase and superoxide dismutase in stroke-prone SHR. Hypertension 2001; 38(3 Pt 2): 606-11.
[http://dx.doi.org/10.1161/hy09t1.094005] [PMID: 11566940]
-100Shah ZA, Li RC, Ahmad AS, et al. The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway. J Cereb Blood Flow Metab 2010; 30(12): 1951-61.
[http://dx.doi.org/10.1038/jcbfm.2010.53] [PMID: 20442725]
]. Moreover, Resveratrol, Apelin, Melatonin, and Minocycline have been successfully used for alleviation of stroke [101Sinha K, Chaudhary G, Gupta YK. Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life Sci 2002; 71(6): 655-65.
[http://dx.doi.org/10.1016/S0024-3205(02)01691-0] [PMID: 12072154]
-104Morimoto N, Shimazawa M, Yamashima T, Nagai H, Hara H. Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res 2005; 1044(1): 8-15.
[http://dx.doi.org/10.1016/j.brainres.2005.02.062] [PMID: 15862784]
].

CONCLUSION

Stroke is a serious disease that causes many disabilities and mortalities. Many scientists are looking for new strategies to control the diseases' concerns. Here, the different progress in managing stroke was introduced. Some were applicable in clinical practices and some of them are not applicable in clinical practices. This progress introduces new horizons for the treatment of stroke and suggests that, for treatment of stroke, application of more than one strategy will protect more effectively the victims of stroke.

LIST OF ABBREVIATIONS

RIC = Remote Ischemic Preconditioning
ROS = Reactive Oxygen Species
Bcl = B-cell lymphoma-extra-large
SVZ = Subventricular Zone of the lateral ventricle
OB = Olfactory Bulb
RMS = Rostral Migratory Stream
TGFα = Transforming Growth Factor α
EGF/bFGF = Epithelial Growth Factor and basic Fibroblast Growth Factor (EGF/bFGF)
BDNF = Brain-derived Neurotrophic Factor
IGF-I = Insulin-like Growth Factor I
IL = Interleukin
NO = Nitric Oxide
BBB = Blood-brain Barrier

AUTHORS' CONTRIBUTIONS

This work has been completed in collaboration with the two authors. Author HF has been provided the title and has been collected the relevant articles and has been written the first draft of the manuscript with the help of Author MK.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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