Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options

Emine Sekerdag, Ihsan Solaroglu, Yasemin Gursoy-Ozdemir, Emine Sekerdag, Ihsan Solaroglu, Yasemin Gursoy-Ozdemir

Abstract

As a result of ischemia or hemorrhage, blood supply to neurons is disrupted which subsequently promotes a cascade of pathophysiological responses resulting in cell loss. Many mechanisms are involved solely or in combination in this disorder including excitotoxicity, mitochondrial death pathways, and the release of free radicals, protein misfolding, apoptosis, necrosis, autophagy and inflammation. Besides neuronal cell loss, damage to and loss of astrocytes as well as injury to white matter contributes also to cerebral injury. The core problem in stroke is the loss of neuronal cells which makes recovery difficult or even not possible in the late states. Acute treatment options that can be applied for stroke are mainly targeting re-establishment of blood flow and hence, their use is limited due to the effective time window of thrombolytic agents. However, if the acute time window is exceeded, neuronal loss starts due to the activation of cell death pathways. This review will explore the most updated cellular death mechanisms leading to neuronal loss in stroke. Ischemic and hemorrhagic stroke as well as subarachnoid hemorrhage will be debated in the light of cell death mechanisms and possible novel molecular and cellular treatment options will be discussed.

Keywords: Ischemic stroke; apoptosis; autophagy; hemorrhagic stroke; necrosis; neuroprotective therapies; pyroptosis..

Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Figures

Fig. (1)
Fig. (1)
The axon terminal of a neuron with membrane transporters and intracellular components which are prone to excitotoxicity.
Fig. (2)
Fig. (2)
Schematic overview of different and complex cell death pathways involved in stroke.

References

    1. Feigin V.L., Forouzanfar M.H., Krishnamurthi R., Mensah G.A., Connor M., Bennett D.A., Moran A.E., Sacco R.L., Anderson L., Truelsen T., O’Donnell M., Venketasubramanian N., Barker-Collo S., Lawes C.M., Wang W., Shinohara Y., Witt E., Ezzati M., Naghavi M., Murray C. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet. 2014;383(9913):245–254. [http://dx.doi. org/10.1016/S0140-6736(13)61953-4]. [PMID: 24449944].
    1. Feigin V.L., Lawes C.M., Bennett D.A., Anderson C.S. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol. 2003;2(1):43–53. []. [PMID: 12849300].
    1. Marier J. Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 1995;333(24):1581–1587. [. 1056/NEJM199512143332401]. [PMID: 7477192].
    1. Hacke W., Lichy C. Thrombolysis for acute stroke under antiplatelet therapy: safe enough to be beneficial? Nat. Clin. Pract. Neurol. 2008;4(9):474–475. [ 0867]. [PMID: 18665145].
    1. Huang J., Upadhyay U.M., Tamargo R.J. Inflammation in stroke and focal cerebral ischemia. Surg. Neurol. 2006;66(3):232–245. []. [PMID: 16935624].
    1. Zhang R., Chopp M., Zhang Z., Jiang N., Powers C. The expression of P- and E-selectins in three models of middle cerebral artery occlusion. Brain Res. 1998;785(2):207–214. [http://dx.doi. org/10.1016/S0006-8993(97)01343-7]. [PMID: 9518615].
    1. Gleichman A.J., Carmichael S.T. Astrocytic therapies for neuronal repair in stroke. Neurosci. Lett. 2014;565:47–52. []. [PMID: 24184876].
    1. George P.M., Steinberg G.K. Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments. Neuron. 2015;87(2):297–309. [. 2015.05.041]. [PMID: 26182415].
    1. Pagnussat A.S., Faccioni-Heuser M.C., Netto C.A., Achaval M. An ultrastructural study of cell death in the CA1 pyramidal field of the hippocapmus in rats submitted to transient global ischemia followed by reperfusion. J. Anat. 2007;211(5):589–599. [http://dx. ]. [PMID: 17784936].
    1. Szydlowska K., Tymianski M. Calcium, ischemia and excitotoxicity. Cell Calcium. 2010;47(2):122–129. [ j.ceca.2010.01.003]. [PMID: 20167368].
    1. Siesjö B.K., Bengtsson F. Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis. J. Cereb. Blood Flow Metab. 1989;9(2):127–140. [ jcbfm.1989.20]. [PMID: 2537841].
    1. Bano D., Nicotera P. Ca2+ signals and neuronal death in brain ischemia. Stroke. 2007;38(2) Suppl.:674–676. [ 10.1161/01.STR.0000256294.46009.29]. [PMID: 17261713].
    1. Anagli J., Han Y., Stewart L., Yang D., Movsisyan A., Abounit K.A. novel calpastatin-based inhibitor improves postischemic neurological recovery. Biochem. Biophys. Res. Commun. 2009;385(1):94–99. [].
    1. Goll D.E., Thompson V.F., Li H., Wei W., Cong J. The calpain system. Physiol. Rev. 2003;83(3):731–801. [. 1152/physrev.00029.2002]. [PMID: 12843408].
    1. Betts R., Weinsheimer S., Blouse G.E., Anagli J. Structural determinants of the calpain inhibitory activity of calpastatin peptide B27-WT. J. Biol. Chem. 2003;278(10):7800–7809. [http://dx.doi. org/10.1074/jbc.M208350200]. [PMID: 12500971].
    1. Wendt A., Thompson V.F., Goll D.E. Interaction of calpastatin with calpain: a review. Biol. Chem. 2004;385(6):465–472. [http:// ]. [PMID: 15255177].
    1. Rama R., García J.C. 2016.
    1. Berliocchi L., Bano D., Nicotera P. Ca2+ signals and death programmes in neurons. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2005;360(1464):2255–2258. [. 1765]. [PMID: 16321795].
    1. Friedman L.K. Calcium: a role for neuroprotection and sustained adaptation. Mol. Interv. 2006;6(6):315–329. [ 10.1124/mi.6.6.5]. [PMID: 17200459].
    1. Xu C., Bailly-Maitre B., Reed J.C. Endoplasmic reticulum stress: cell life and death decisions. J. Clin. Invest. 2005;115(10):2656–2664. [].
    1. Urano F., Wang X., Bertolotti A., Zhang Y., Chung P., Harding H.P., Ron D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287(5453):664–666. [. 5453.664]. [PMID: 10650002].
    1. Bodalia A., Li H., Jackson M.F. Loss of endoplasmic reticulum Ca2+ homeostasis: contribution to neuronal cell death during cerebral ischemia. Acta Pharmacol. Sin. 2013;34(1):49–59. [http://dx. ]. [PMID: 23103622].
    1. Su Y., Li F. Endoplasmic reticulum stress in brain ischemia. 2016.
    1. Rashid H-O., Yadav R.K., Kim H-R, Chae H-J. E.R. 2015.
    1. Cai Y., Arikkath J., Yang L., Guo M-L., Periyasamy P., Buch S. Interplay of endoplasmic reticulum stress and autophagy in neurodegenerative disorders. 2016.
    1. Zhang X., Yuan Y., Jiang L., Zhang J., Gao J., Shen Z. Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury. 2014.
    1. Sheng R., Liu X-Q., Zhang L-S., Gao B., Han R., Wu Y-Q., Zhang X.Y., Qin Z.H. Autophagy regulates endoplasmic reticulum stress in ischemic preconditioning. Autophagy. 2012;8(3):310–325. []. [PMID: 22361585].
    1. Kouroku Y., Fujita E., Tanida I., Ueno T., Isoai A., Kumagai H., Ogawa S., Kaufman R.J., Kominami E., Momoi T. ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 2007;14(2):230–239. [. 1038/sj.cdd.4401984]. [PMID: 16794605].
    1. Tajiri S., Oyadomari S., Yano S., Morioka M., Gotoh T., Hamada J.I., Ushio Y., Mori M. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ. 2004;11(4):403–415. [http:// ]. [PMID: 14752508].
    1. Friberg H., Wieloch T. Mitochondrial permeability transition in acute neurodegeneration. Biochimie. 2001;84(2–3):241–250. [].
    1. Kalogeris T., Bao Y., Korthuis R.J. Mitochondrial reactive oxygen species: A double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol. 2014;2:702–714.
    1. Manzanero S., Santro T., Arumugam T.V. Neuronal oxidative stress in acute ischemic stroke: Sources and contribution to cell injury. Neurochem. Int. 2013;62(5):712–718.
    1. Yamashima T. Ca2+-dependent proteases in ischemic neuronal death: a conserved ‘calpain-cathepsin cascade’ from nematodes to primates. Cell Calcium. 2004;36(3-4):285–293. [ 10.1016/j.ceca.2004.03.001]. [PMID: 15261484].
    1. Rostas J.A.P., Hoffman A., Murtha L.A., Pepperall D., McLeod D.D., Dickson P.W. Ischaemia- and excitotoxicity-induced CaMKII-mediated neuronal cell death: The relative roles of CaMKII auto-phosphorylation at T286 and T253. Neurochem. Int. 2017;104:6–10.
    1. Chen R., Gong P., Tao T., Gao Y., Shen J., Yan Y., Duan C., Wang J., Liu X. O-GlcNAc glycosylation of nNOS promotes neuronal apoptosis following glutamate excitotoxicity. Cell. Mol. Neurobiol. 2017;37(8):1465–1475. []. [PMID: 28238085].
    1. Roy-O’Reilly M., McCullough L.D. Astrocytes fuel the fire of lymphocyte toxicity after stroke. Proc. Natl. Acad. Sci. USA. 2017;114(3):425–427. []. [PMID: 28062689].
    1. Kaushal V., Schlichter L.C. Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. J. Neurosci. 2008;28(9):2221–2230. [. 5643-07.2008]. [PMID: 18305255].
    1. Stys P.K. White matter injury Mechanisms. Curr. Mol. Med. 2004;4(2):113–130. [].
    1. Baxter P., Chen Y., Xu Y., Swanson R.A. Mitochondrial dysfunction induced by nuclear poly(ADP-ribose) polymerase-1: a treatable cause of cell death in stroke. Transl. Stroke Res. 2014;5(1):136–144. []. [PMID: 24323707].
    1. van der Burgh R., Boes M. Mitochondria in autoinflammation: cause, mediator or bystander? Trends Endocrinol. Metab. 2015;26(5):263–271. []. [PMID: 25850613].
    1. Iadecola C., Anrather J. The immunology of stroke: from mechanisms to translation. Nat. Med. 2011;17(7):796–808. [http://dx. ]. [PMID: 21738161].
    1. Li M., Li Z., Yao Y., Jin W-N., Wood K., Liu Q., Shi F.D., Hao J. Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity. Proc. Natl. Acad. Sci. USA. 2017;114(3):E396–E405. [ pnas.1612930114]. [PMID: 27994144].
    1. Felger J.C., Abe T., Kaunzner U.W., Gottfried-Blackmore A., Gal-Toth J., McEwen B.S. Brain dendritic cells in ischemic stroke: Time course, activation state, and origin. Brain Behav. Immun. 2010;24(5):724–737.
    1. Yilmaz G., Granger D.N. Cell adhesion molecules and ischemic stroke. Neurol. Res. 2008;30(8):783–793. [ 10.1179/174313208X341085]. [PMID: 18826804].
    1. Arumugam T.V., Granger D.N., Mattson M.P. Stroke and T-cells. Neuromolecular Med. 2005;7(3):229–242. [http://dx.doi. org/10.1385/NMM:7:3:229]. [PMID: 16247183].
    1. Hurn P.D., Subramanian S., Parker S.M., Afentoulis M.E., Kaler L.J., Vandenbark A.A., Offner H. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J. Cereb. Blood Flow Metab. 2007;27(11):1798–1805. []. [PMID: 17392692].
    1. Ponomarev E.D., Shriver L.P., Maresz K., Dittel B.N. Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J. Neurosci. Res. 2005;81(3):374–389. [http://dx. ]. [PMID: 15959904].
    1. Suzuki Y., Hattori K., Hamanaka J., Murase T., Egashira Y., Mishiro K., Ishiguro M., Tsuruma K., Hirose Y., Tanaka H., Yoshimura S., Shimazawa M., Inagaki N., Nagasawa H., Iwama T., Hara H. Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia. Sci. Rep. 2012;2:896. []. [PMID: 23193438].
    1. Shichita T., Hasegawa E., Kimura A., Morita R., Sakaguchi R., Takada I., Sekiya T., Ooboshi H., Kitazono T., Yanagawa T., Ishii T., Takahashi H., Mori S., Nishibori M., Kuroda K., Akira S., Miyake K., Yoshimura A. Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain. Nat. Med. 2012;18(6):911–917. []. [PMID: 22610280].
    1. Ruhnau J., Schulze J., Dressel A., Vogelgesang A. Thrombosis, neuroinflammation, and poststroke infection: The multifaceted role of neutrophils in stroke. J. Immunol. Res. 2017;2017:5140679. doi: 10.1155/2017/5140679.
    1. Ruhnau J., Schulze J., Dressel A., Vogelgesang A. Neutrophils as a therapeutic target in stroke. 2017.
    1. Swanson R.A., Ying W., Kauppinen T.M. Astrocyte Influences on Ischemic Neuronal Death. Curr. Mol. Med. 2004;4(2):193–205. [].
    1. Shaafi S., Sharifipour E., Rahmanifar R., Hejazi S., Andalib S., Nikanfar M., Baradarn B., Mehdizadeh R. Interleukin-6, a reliable prognostic factor for ischemic stroke. Iran. J. Neurol. 2014;13(2):70–76. [PMID: 25295149].
    1. Chen Y., Hallenbeck J.M., Ruetzler C., Bol D., Thomas K., Berman N.E.J., Vogel S.N. Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells. J. Cereb. Blood Flow Metab. 2003;23(6):748–755. [ 10.1097/01.WCB.0000071885.63724.20]. [PMID: 12796723].
    1. Mojsilovic-Petrovic J., Callaghan D., Cui H., Dean C., Stanimirovic D.B., Zhang W. Hypoxia-inducible factor-1 (HIF-1) is involved in the regulation of hypoxia-stimulated expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and MCP-5 (Ccl12) in astrocytes. J. Neuroinflammation. 2007;4(1):12. [ 10.1186/1742-2094-4-12]. [PMID: 17474992].
    1. Cheung E.C.C., Melanson-Drapeau L., Cregan S.P., Vanderluit J.L., Ferguson K.L., McIntosh W.C., Park D.S., Bennett S.A., Slack R.S. Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms. J. Neurosci. 2005;25(6):1324–1334. [http://dx. ]. [PMID: 15703386].
    1. Zuo W., Yang P.F., Chen J., Zhang Z., Chen N.H. Drp-1, a potential therapeutic target for brain ischaemic stroke. Br. J. Pharmacol. 2016;173(10):1665–1677. [. 13468]. [PMID: 26915692].
    1. Pradeep H., Sharma B., Rajanikant G.K. Drp1 in Ischemic neuronal death: An unusual suspect. Curr. Med. Chem. 2014;21(19):2183–2189.
    1. Song B., Ao Q., Wang Z., Liu W., Niu Y., Shen Q., Zuo H., Zhang X., Gong Y. Phosphorylation of tau protein over time in rats subjected to transient brain ischemia. Neural Regen. Res. 2013;8(34):3173–3182. [PMID: 25206638].
    1. Wen Y., Yang S., Liu R., Simpkins J.W. Transient cerebral ischemia induces site-specific hyperphosphorylation of tau protein. Brain Res. 2004;1022(1-2):30–38. [ j.brainres.2004.05.106]. [PMID: 15353210].
    1. Chen X., Liu Y., Zhu J., Lei S., Dong Y., Li L. GSK-3β downregulates Nrf2 in cultured cortical neurons and in a rat model of cerebral ischemia-reperfusion. Sci. Rep. 2016;6:20196.
    1. Jo C., Gundemir S., Pritchard S., Jin Y.N., Rahman I., Johnson G.V. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat. Commun. 2014;5:3496. []. [PMID: 24667209].
    1. Wu H., Che X., Zheng Q., Wu A., Pan K., Shao A., Wu Q., Zhang J., Hong Y. Caspases: a molecular switch node in the crosstalk between autophagy and apoptosis. Int. J. Biol. Sci. 2014;10(9):1072–1083. []. [PMID: 25285039].
    1. Sabri M., Lass E. Macdonald, RL Early brain injury: a common mechanism in subarachnoid hemorrhage and global cerebral ischemia. Stroke Res. Treat. 2013;2013:394036. [http://dx. ].
    1. D’Orsi B., Mateyka J., Prehn J.H.M. Control of mitochondrial physiology and cell death by the Bcl-2 family proteins Bax and Bok. Neurochem. Int. 2017;109:162–170. [ 10.1016/j.neuint.2017.03.010]. [PMID: 28315370].
    1. Danial N.N., Korsmeyer S.J. Cell death: critical control points. Cell. 2004;116(2):205–219. []. [PMID: 14744432].
    1. Youle R.J., Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 2008;9(1):47–59. []. [PMID: 18097445].
    1. D’Orsi B., Kilbride S.M., Chen G., Perez Alvarez S., Bonner H.P., Pfeiffer S., Plesnila N., Engel T., Henshall D.C., Düssmann H., Prehn J.H. Bax regulates neuronal Ca2+ homeostasis. J. Neurosci. 2015;35(4):1706–1722. [ JNEUROSCI.2453-14.2015]. [PMID: 25632145].
    1. D’Orsi B., Engel T., Pfeiffer S., Nandi S., Kaufmann T., Henshall D.C., Prehn J.H. Bok is not pro-apoptotic but suppresses poly ADP-ribose polymerase-dependent cell death pathways and protects against excitotoxic and seizure-induced neuronal injury. J. Neurosci. 2016;36(16):4564–4578. [ JNEUROSCI.3780-15.2016]. [PMID: 27098698].
    1. Kim T., Vemuganti R. Mechanisms of Parkinson’s disease-related proteins in mediating secondary brain damage after cerebral ischemia. J. Cereb. Blood Flow Metab. 2017;37(6):1910–1926. [].
    1. Yoon D-K., Hwang I.K., Yoo K-Y., Lee Y-B., Lee J-J., Kim J-H., Kang T.C., Lee B.H., Sohn H.S., Won M.H. Comparison of α-synuclein immunoreactivity and protein levels in ischemic hippocampal CA1 region between adult and aged gerbils and correlation with Cu,Zn-superoxide dismutase. Neurosci. Res. 2006;55(4):434–441. []. [PMID: 16759729].
    1. Kim T., Mehta S.L., Kaimal B., Lyons K., Dempsey R.J., Vemuganti R. Poststroke induction of α-synuclein mediates ischemic brain damage. J. Neurosci. 2016;36(26):7055–7065. [http://dx. ]. [PMID: 27358461].
    1. Zhou M., Xia Z.Y., Lei S.Q., Leng Y., Xue R. Role of mitophagy regulated by Parkin/DJ-1 in remote ischemic postconditioning-induced mitigation of focal cerebral ischemia-reperfusion. Eur. Rev. Med. Pharmacol. Sci. 2015;19(24):4866–4871. [PMID: 26744879].
    1. Yanagisawa D., Kitamura Y., Inden M., Takata K., Taniguchi T., Morikawa S., Morita M., Inubushi T., Tooyama I., Taira T., Iguchi-Ariga S.M., Akaike A., Ariga H. DJ-1 protects against neurodegeneration caused by focal cerebral ischemia and reperfusion in rats. J. Cereb. Blood Flow Metab. 2008;28(3):563–578. []. [PMID: 17882163].
    1. Kitamura Y., Watanabe S., Taguchi M., Takagi K., Kawata T., Takahashi-Niki K., Yasui H., Maita H., Iguchi-Ariga S.M., Ariga H. Neuroprotective effect of a new DJ-1-binding compound against neurodegeneration in Parkinson’s disease and stroke model rats. Mol. Neurodegener. 2011;6(1):48. [ 10.1186/1750-1326-6-48]. [PMID: 21740546].
    1. Yu H.H., Xu Q., Chen H.P., Wang S., Huang X.S., Huang Q.R., He M. Stable overexpression of DJ-1 protects H9c2 cells against oxidative stress under a hypoxia condition. Cell Biochem. Funct. 2013;31(8):643–651. []. [PMID: 23281015].
    1. Aleyasin H., Rousseaux M.W., Phillips M., Kim R.H., Bland R.J., Callaghan S., Slack R.S., During M.J., Mak T.W., Park D.S. The Parkinson’s disease gene DJ-1 is also a key regulator of stroke-induced damage. Proc. Natl. Acad. Sci. USA. 2007;104(47):18748–18753. []. [PMID: 18003894].
    1. Zhao Y., Chen F., Chen S., Liu X., Cui M., Dong Q. The Parkinson’s disease-associated gene PINK1 protects neurons from ischemic damage by decreasing mitochondrial translocation of the fission promoter Drp1. J. Neurochem. 2013;127(5):711–722. []. [PMID: 23772688].
    1. Huang Y., Chen H., Zhu J., Zhao F., Qu Y., Mu D. Effects of PINK1 gene on cell apoptosis and cell autophagy in neonatal mice with hypoxic-ischemic brain damage Zhongguo dang dai er ke za zhi. Chinese J. Contemp. Pediatr. 2016;18(3):263–269.
    1. Chen S-D., Lin T-K., Yang D-I., Lee S-Y., Shaw F-Z., Liou C-W., Chuang Y.C. Roles of PTEN-induced putative kinase 1 and dynamin-related protein 1 in transient global ischemia-induced hippocampal neuronal injury. Biochem. Biophys. Res. Commun. 2015;460(2):397–403. [. 045]. [PMID: 25791474].
    1. Edinger A.L., Thompson C.B. Death by design: apoptosis, necrosis and autophagy. Curr. Opin. Cell Biol. 2004;16(6):663–669. []. [PMID: 15530778].
    1. Gürer G., Gursoy-Ozdemir Y., Erdemli E., Can A., Dalkara T. Astrocytes are more resistant to focal cerebral ischemia than neurons and die by a delayed necrosis. Brain Pathol. 2009;19(4):630–641. []. [PMID: 18947334].
    1. Zhou W., Yuan J., editors. Necroptosis in health and diseases. Semin. Cell. Develop. Biol. Elsevier; 2014.
    1. Linkermann A., Green D.R. Necroptosis. N. Engl. J. Med. 2014;370(5):455–465. []. [PMID: 24476434].
    1. Kilinc M., Gürsoy-Ozdemir Y., Gürer G., Erdener S.E., Erdemli E., Can A., Dalkara T. Lysosomal rupture, necroapoptotic interactions and potential crosstalk between cysteine proteases in neurons shortly after focal ischemia. Neurobiol. Dis. 2010;40(1):293–302. []. [PMID: 20600913].
    1. Ünal-Çevik I., Kilinç M., Can A., Gürsoy-Ozdemir Y., Dalkara T. Apoptotic and necrotic death mechanisms are concomitantly activated in the same cell after cerebral ischemia. Stroke. 2004;35(9):2189–2194. [. c5]. [PMID: 15256676].
    1. Degterev A., Huang Z., Boyce M., Li Y., Jagtap P., Mizushima N., Cuny G.D., Mitchison T.J., Moskowitz M.A., Yuan J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 2005;1(2):112–119. []. [PMID: 16408008].
    1. Holler N., Zaru R., Micheau O., Thome M., Attinger A., Valitutti S., Bodmer J.L., Schneider P., Seed B., Tschopp J. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 2000;1(6):489–495. []. [PMID: 11101870].
    1. Degterev A., Hitomi J., Germscheid M., Ch’en I.L., Korkina O., Teng X., Abbott D., Cuny G.D., Yuan C., Wagner G., Hedrick S.M., Gerber S.A., Lugovskoy A., Yuan J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 2008;4(5):313–321. []. [PMID: 18408713].
    1. Hitomi J., Christofferson D.E., Ng A., Yao J., Degterev A., Xavier R.J., Yuan J. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008;135(7):1311–1323. [. 044]. [PMID: 19109899].
    1. Baines C.P. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008;135(7):1311–1323. [].
    1. Xie Y., Hou W., Song X., Yu Y., Huang J., Sun X. Ferroptosis: process and function. 2016.
    1. Zille M., Karuppagounder S.S., Chen Y., Gough P.J., Bertin J., Finger J., Milner T.A., Jonas E.A., Ratan R.R. Neuronal death after hemorrhagic stroke in vitro and in vivo shares features of ferroptosis and necroptosis. Stroke. 2017;48(4):1033–1043. []. [PMID: 28250197].
    1. Rubinsztein D.C., Bento C.F., Deretic V. Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J. Exp. Med. 2015;212(7):979–990. [].
    1. Ginet V., Spiehlmann A., Rummel C., Rudinskiy N., Grishchuk Y., Luthi-Carter R., Clarke P.G., Truttmann A.C., Puyal J. Involvement of autophagy in hypoxic-excitotoxic neuronal death. Autophagy. 2014;10(5):846–860. [. 28264]. [PMID: 24674959].
    1. Parzych K.R., Klionsky D.J. An overview of autophagy: morphology, mechanism, and regulation. Antioxid. Redox Signal. 2014;20(3):460–473. [].
    1. Huang X.P., Ding H., Lu J.D., Tang Y.H., Deng B.X., Deng C.Q. Autophagy in cerebral ischemia and the effects of traditional Chinese medicine. J. Integr. Med. 2015;13(5):289–296. [http://dx. ]. [PMID: 26343099].
    1. Chang P., Dong W., Zhang M., Wang Z., Wang Y., Wang T., Gao Y., Meng H., Luo B., Luo C., Chen X., Tao L. Anti-necroptosis chemical necrostatin-1 can also suppress apoptotic and autophagic pathway to exert neuroprotective effect in mice intracerebral hemorrhage model. J. Mol. Neurosci. 2014;52(2):242–249. []. [PMID: 24122153].
    1. Chen S., Wu H., Tang J., Zhang J., Zhang J.H. Neurovascular events after subarachnoid hemorrhage: focusing on subcellular organelles. Neurovascular Events After Subarachnoid Hemorrhage. Springer; 2015. pp. 39–46. []
    1. Zhang X., Yan H., Yuan Y., Gao J., Shen Z., Cheng Y., Shen Y., Wang R.R., Wang X., Hu W.W., Wang G., Chen Z. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy. 2013;9(9):1321–1333. []. [PMID: 23800795].
    1. Frugier T., Taylor J.M., McLean C., Bye N., Beart P.M., Devenish R.J., Crack P.J. Evidence for the recruitment of autophagic vesicles in human brain after stroke. Neurochem. Int. 2016;96:62–68. []. [PMID: 26930584].
    1. Yang Z., Zhao T.Z., Zou Y.J., Zhang J.H., Feng H. Hypoxia Induces autophagic cell death through hypoxia-inducible factor 1α in microglia. PLoS One. 2014;9(5):e96509. [ 10.1371/journal.pone.0096509]. [PMID: 24818601].
    1. Pamenter M.E., Perkins G.A., McGinness A.K., Gu X.Q., Ellisman M.H., Haddad G.G. Autophagy and apoptosis are differentially induced in neurons and astrocytes treated with an in vitro mimic of the ischemic penumbra. PLoS One. 2012;7(12):e51469. []. [PMID: 23251543].
    1. Carloni S., Buonocore G., Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol. Dis. 2008;32(3):329–339. [. 2008.07.022]. [PMID: 18760364].
    1. Dunlop E., Tee A. mTOR and autophagy: a dynamic relationship governed by nutrients and energy; Elsevier. Semin. Cell Dev. Biol. 2014;36:121–129.
    1. Alers S., Löffler A.S., Wesselborg S., Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol. Cell. Biol. 2012;32(1):2–11. [http://dx.doi. org/10.1128/MCB.06159-11]. [PMID: 22025673].
    1. Tang Y-C., Tian H-X., Yi T., Chen H-B. The critical roles of mitophagy in cerebral ischemia. Protein Cell. 2016;7(10):699–713. []. [PMID: 27554669].
    1. Bakhshayesh B., Hosseininezhad M., Saadat S.N., Ansar M.M., Ramezani H., Saadat S.M. Iron overload is associated with perihematoma edema growth following intracerebral hemorrhage that may contribute to in-hospital mortality and long-term functional outcome. Curr. Neurovasc. Res. 2014;11(3):248–253. [http:// ]. [PMID: 24875488].
    1. Mancias J.D., Wang X., Gygi S.P., Harper J.W., Kimmelman A.C. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature. 2014;509(7498):105–109. []. [PMID: 24695223].
    1. Qin A-P., Liu C-F., Qin Y-Y., Hong L-Z., Xu M., Yang L., Liu J., Qin Z.H., Zhang H.L. Autophagy was activated in injured astrocytes and mildly decreased cell survival following glucose and oxygen deprivation and focal cerebral ischemia. Autophagy. 2010;6(6):738–753. []. [PMID: 20574158].
    1. Zhou X-Y., Luo Y., Zhu Y-M., Liu Z-H., Kent T.A., Rong J-G., Li W., Qiao S.G., Li M., Ni Y., Ishidoh K., Zhang H.L. Inhibition of autophagy blocks cathepsins-tBid-mitochondrial apoptotic signaling pathway via stabilization of lysosomal membrane in ischemic astrocytes. Cell Death Dis. 2017;8(2):e2618. [http:// ]. [PMID: 28206988].
    1. Song J., Oh Y., Lee J.E. miR-Let7A modulates autophagy induction in LPS-activated microglia. Exp. Neurobiol. 2015;24(2):117–125. []. [PMID: 26113790].
    1. Zhang B., Song C., Feng B., Fan W. Neuroprotection by triptolide against cerebral ischemia/reperfusion injury through the inhibition of NF-κB/PUMA signal in rats. Ther. Clin. Risk Manag. 2016;12:817–824. []. [PMID: 27307742].
    1. Weis S.N., Toniazzo A.P., Ander B.P., Zhan X., Careaga M., Ashwood P. Autophagy in the brain of neonates following hypoxia–ischemia shows sex- and region-specific effects. Neuroscience. 2014;256:201–209.
    1. Bergsbaken T., Fink S.L., Cookson B.T. Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol. 2009;7(2):99–109. []. [PMID: 19148178].
    1. Fink S.L., Bergsbaken T., Cookson B.T. Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanisms. Proc. Natl. Acad. Sci. USA. 2008;105(11):4312–4317. [ pnas.0707370105]. [PMID: 18337499].
    1. Brennan M.A., Cookson B.T. Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol. Microbiol. 2000;38(1):31–40. []. [PMID: 11029688].
    1. Chen G.Y., Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 2010;10(12):826–837. [http://dx. ]. [PMID: 21088683].
    1. Abulafia D.P., de Rivero Vaccari J.P., Lozano J.D., Lotocki G., Keane R.W., Dietrich W.D. Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J. Cereb. Blood Flow Metab. 2009;29(3):534–544. []. [PMID: 19066616].
    1. Tang S-C., Arumugam T.V., Xu X., Cheng A., Mughal M.R., Jo D.G., Lathia J.D., Siler D.A., Chigurupati S., Ouyang X., Magnus T., Camandola S., Mattson M.P. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc. Natl. Acad. Sci. USA. 2007;104(34):13798–13803. []. [PMID: 17693552].
    1. Schroder K., Tschopp J. The inflammasomes. Cell. 2010;140(6):821–832. []. [PMID: 20303873].
    1. Tschopp J., Schroder K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 2010;10(3):210–215. [. 1038/nri2725]. [PMID: 20168318].
    1. Mulcahy N.J., Ross J., Rothwell N.J., Loddick S.A. Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat. Br. J. Pharmacol. 2003;140(3):471–476. []. [PMID: 12970087].
    1. Martinon F., Burns K., Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell. 2002;10(2):417–426. [http://dx. ]. [PMID: 12191486].
    1. Fann D.Y-W., Lee S.Y., Manzanero S., Tang S-C., Gelderblom M., Chunduri P., Bernreuther C., Glatzel M., Cheng Y.L., Thundyil J., Widiapradja A., Lok K.Z., Foo S.L., Wang Y.C., Li Y.I., Drummond G.R., Basta M., Magnus T., Jo D.G., Mattson M.P., Sobey C.G., Arumugam T.V. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013;4(9):e790. []. [PMID: 24008734].
    1. Barrington J., Lemarchand E., Allan S.M. A brain in flame; do inflammasomes and pyroptosis influence stroke pathology? Brain Pathol. 2016 [PMID: 27997059].
    1. Fann DY-W, Lee S-Y, Manzanero S, Chunduri P, Sobey CG, Arumugam TV. Pathogenesis of acute stroke and the role of inflammasomes. 2013.
    1. Pearson V.L., Rothwell N.J., Toulmond S. Excitotoxic brain damage in the rat induces interleukin-1β protein in microglia and astrocytes: correlation with the progression of cell death. Glia. 1999;25(4):311–323. [ (19990215)25:4<311:AID-GLIA1>;2-E]. [PMID: 10028914].
    1. Denes A., Lopez-Castejon G., Brough D. Caspase-1: is IL-1 just the tip of the ICEberg? Cell Death Dis. 2012;3(7):e338. []. [PMID: 22764097].
    1. Fink S.L., Cookson B.T. Caspase-1-dependent pore formation during pyroptosis leads to osmotic lysis of infected host macrophages. Cell. Microbiol. 2006;8(11):1812–1825. [http://dx.doi. org/10.1111/j.1462-5822.2006.00751.x]. [PMID: 16824040].
    1. Miao E.A., Rajan J.V., Aderem A. Caspase-1-induced pyroptotic cell death. Immunol. Rev. 2011;243(1):206–214. [http://dx.doi. org/10.1111/j.1600-065X.2011.01044.x]. [PMID: 21884178].
    1. Rabuffetti M., Sciorati C., Tarozzo G., Clementi E., Manfredi A.A., Beltramo M. Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of pro inflammatory cytokines. J. Neurosci. 2000;20(12):4398–4404. [. 2000]. [PMID: 10844008].
    1. Ray A.M., Owen D.E., Evans M.L., Davis J.B., Benham C.D. Caspase inhibitors are functionally neuroprotective against oxygen glucose deprivation induced CA1 death in rat organotypic hippocampal slices. Brain Res. 2000;867(1-2):62–69. [ 10.1016/S0006-8993(00)02230-7]. [PMID: 10837798].
    1. Kang S-J., Wang S., Hara H., Peterson E.P., Namura S., Amin-Hanjani S., Huang Z., Srinivasan A., Tomaselli K.J., Thornberry N.A., Moskowitz M.A., Yuan J. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell Biol. 2000;149(3):613–622. [ 10.1083/jcb.149.3.613]. [PMID: 10791975].
    1. Siniscalchi A., Gallelli L., Malferrari G., Pirritano D., Serra R., Santangelo E., De Sarro G. Cerebral stroke injury: the role of cytokines and brain inflammation. J. Basic Clin. Physiol. Pharmacol. 2014;25(2):131–137. []. [PMID: 24515999].
    1. Ekdahl C.T., Kokaia Z., Lindvall O. 2009.
    1. Barreto G.E., White R., Ouyang Y., Xu L. G Giffard R. Astrocytes: targets for neuroprotection in stroke. Central nervous system agents in medicinal chemistry (Formerly Current Medicinal Chemistry-Central Nervous System Agents). CNSAMC. 2011;11(2):164–173.
    1. Wood P.L. Microglia as a unique cellular target in the treatment of stroke: potential neurotoxic mediators produced by activated microglia. Neurol. Res. 1995;17(4):242–248. [. 1080/01616412.1995.11740321]. [PMID: 7477737].
    1. Patel A.R., Ritzel R., McCullough L.D., Liu F. Microglia and ischemic stroke: a double-edged sword. Int. J. Physiol. Pathophysiol. Pharmacol. 2013;5(2):73–90. [PMID: 23750306].
    1. Jin R., Yang G., Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J. Leukoc. Biol. 2010;87(5):779–789. []. [PMID: 20130219].
    1. Giulian D., Vaca K. Inflammatory glia mediate delayed neuronal damage after ischemia in the central nervous system. Stroke. 1993;24(12) Suppl.:I84–I90. [PMID: 8249026].
    1. Gelderblom M., Leypoldt F., Steinbach K., Behrens D., Choe C-U., Siler D.A., Arumugam T.V., Orthey E., Gerloff C., Tolosa E., Magnus T. Temporal and spatial dynamics of cerebral immune cell accumulation in stroke. Stroke. 2009;40(5):1849–1857. []. [PMID: 19265055].
    1. Rodríguez-Yáñez M., Castillo J. Role of inflammatory markers in brain ischemia. Curr. Opin. Neurol. 2008;21(3):353–357. [http:// ]. [PMID: 18451722].
    1. Nakase T., Yamazaki T., Ogura N., Suzuki A., Nagata K. The impact of inflammation on the pathogenesis and prognosis of ischemic stroke. J. Neurol. Sci. 2008;271(1-2):104–109. []. [PMID: 18479710].
    1. Beridze M., Sanikidze T., Shakarishvili R., Intskirveli N., Bornstein N.M. Selected acute phase CSF factors in ischemic stroke: findings and prognostic value. BMC Neurol. 2011;11(1):41. []. [PMID: 21450100].
    1. Maki T, Hayakawa K, Pham L-DD, Xing C, Lo EH. 2013.
    1. Arai K., Lok J., Guo S., Hayakawa K., Xing C., Lo E.H. Cellular mechanisms of neurovascular damage and repair after stroke. J. Child Neurol. 2011;26(9):1193–1198. [ 0883073811408610]. [PMID: 21628695].
    1. Xing C., Hayakawa K., Lok J., Arai K., Lo E.H. Injury and repair in the neurovascular unit. Neurol. Res. 2012;34(4):325–330. []. [PMID: 22643075].
    1. Fagan S.C., Hess D.C., Hohnadel E.J., Pollock D.M., Ergul A. Targets for vascular protection after acute ischemic stroke. Stroke. 2004;35(9):2220–2225. [. 0000138023.60272.9e]. [PMID: 15284446].
    1. Hansen T.M., Moss A.J., Brindle N.P. Vascular endothelial growth factor and angiopoietins in neurovascular regeneration and protection following stroke. Curr. Neurovasc. Res. 2008;5(4):236–245. []. [PMID: 18991658].
    1. Kassis H., Shehadah A., Chopp M., Zhang Z.G. Epigenetics in Stroke Recovery. Genes (Basel) 2017;8(3):89. [http://dx.doi. org/10.3390/genes8030089]. [PMID: 28264471].
    1. Hu Z., Zhong B., Tan J., Chen C., Lei Q., Zeng L. The emerging role of epigenetics in cerebral ischemia. Mol. Neurobiol. 2017;54(3):1887–1905. []. [PMID: 26894397].
    1. Hwang J-Y., Aromolaran K.A., Zukin R.S. The emerging field of epigenetics in neurodegeneration and neuroprotection. Nat. Rev. Neurosci. 2017;18(6):347–361. [. 2017.46]. [PMID: 28515491].
    1. Endres M., Meisel A., Biniszkiewicz D., Namura S., Prass K., Ruscher K., Lipski A., Jaenisch R., Moskowitz M.A., Dirnagl U. DNA methyltransferase contributes to delayed ischemic brain injury. J. Neurosci. 2000;20(9):3175–3181. [. 1523/JNEUROSCI.20-09-03175.2000]. [PMID: 10777781].
    1. Endres M., Fan G., Meisel A., Dirnagl U., Jaenisch R. Effects of cerebral ischemia in mice lacking DNA methyltransferase 1 in post-mitotic neurons. Neuroreport. 2001;12(17):3763–3766. []. [PMID: 11726790].
    1. Dock H., Theodorsson A., Theodorsson E. DNA methylation inhibitor zebularine confers stroke protection in ischemic rats. Transl. Stroke Res. 2015;6(4):296–300. [. 1007/s12975-015-0397-7]. [PMID: 25824538].
    1. Jobe E.M., McQuate A.L., Zhao X. Crosstalk among epigenetic pathways regulates neurogenesis. Front. Neurosci. 2012;6:59. []. [PMID: 22586361].
    1. Singh V., Sharma P., Capalash N. DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer. Curr. Cancer Drug Targets. 2013;13(4):379–399. [ 15680096113139990077]. [PMID: 23517596].
    1. Baltan S., Bachleda A., Morrison R.S., Murphy S.P. Expression of histone deacetylases in cellular compartments of the mouse brain and the effects of ischemia. Transl. Stroke Res. 2011;2(3):411–423. []. [PMID: 21966324].
    1. Kim H.J., Rowe M., Ren M., Hong J-S., Chen P-S., Chuang D-M. Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J. Pharmacol. Exp. Ther. 2007;321(3):892–901. []. [PMID: 17371805].
    1. Ren M., Leng Y., Jeong M., Leeds P.R., Chuang D.M. Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J. Neurochem. 2004;89(6):1358–1367. []. [PMID: 15189338].
    1. Kassis H., Chopp M., Liu X.S., Shehadah A., Roberts C., Zhang Z.G. Histone deacetylase expression in white matter oligodendrocytes after stroke. Neurochem. Int. 2014;77:17–23. []. [PMID: 24657831].
    1. Kim H.J., Leeds P., Chuang D.M. The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J. Neurochem. 2009;110(4):1226–1240. []. [PMID: 19549282].
    1. Faraco G., Pancani T., Formentini L., Mascagni P., Fossati G., Leoni F., Moroni F., Chiarugi A. Pharmacological inhibition of histone deacetylases by suberoylanilide hydroxamic acid specifically alters gene expression and reduces ischemic injury in the mouse brain. Mol. Pharmacol. 2006;70(6):1876–1884. []. [PMID: 16946032].
    1. Liu X.S., Chopp M., Zhang R.L., Zhang Z.G. MicroRNAs in cerebral ischemia-induced neurogenesis. J. Neuropathol. Exp. Neurol. 2013;72(8):718–722. [ e31829e4963]. [PMID: 23860031].
    1. Liu X.S., Chopp M., Zhang R.L., Tao T., Wang X.L., Kassis H., Hozeska-Solgot A., Zhang L., Chen C., Zhang Z.G. 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].
    1. Lapchak P.A., Zhang J.H. Neuroprotective Therapy for Stroke and Ischemic Disease. Springer; 2017. [. 1007/978-3-319-45345-3]
    1. Lee J-K., Kim J-E., Sivula M., Strittmatter S.M. Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J. Neurosci. 2004;24(27):6209–6217. [. 1523/JNEUROSCI.1643-04.2004]. [PMID: 15240813].
    1. Murphy T.H., Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat. Rev. Neurosci. 2009;10(12):861–872. []. [PMID: 19888284].
    1. Lindenberg R., Renga V., Zhu L.L., Nair D., Schlaug G. Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients. Neurology. 2010;75(24):2176–2184. [http://dx.doi. org/10.1212/WNL.0b013e318202013a]. [PMID: 21068427].
    1. Levy R., Ruland S., Weinand M., Lowry D., Dafer R., Bakay R. Cortical stimulation for the rehabilitation of patients with hemiparetic stroke: a multicenter feasibility study of safety and efficacy. 2008.
    1. Yamashima T. Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog. Neurobiol. 2000;62(3):273–295. [ 00006-X]. [PMID: 10840150].
    1. Karatas H., Aktas Y., Gursoy-Ozdemir Y., Bodur E., Yemisci M., Caban S., Vural A., Pinarbasli O., Capan Y., Fernandez-Megia E., Novoa-Carballal R., Riguera R., Andrieux K., Couvreur P., Dalkara T. A nanomedicine transports a peptide caspase-3 inhibitor across the blood-brain barrier and provides neuroprotection. J. Neurosci. 2009;29(44):13761–13769. [ 10.1523/JNEUROSCI.4246-09.2009]. [PMID: 19889988].
    1. Deng Y-h., He H-y. Yang, L-q. Zhang, P-y. Dynamic changes in neuronal autophagy and apoptosis in the ischemic penumbra following permanent ischemic stroke. Neural Regen. Res. 2016;11(7):1108–1114.
    1. Yu Z.F., Bruce-Keller A.J., Goodman Y., Mattson M.P. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J. Neurosci. Res. 1998;53(5):613–625. [ (SICI)1097-4547(19980901)53:5<613:AID-JNR11>;2-1]. [PMID: 9726432].
    1. 1999.
    1. Asano T., Mori T., Shimoda T., Shinagawa R., Satoh S., Yada N., Katsumata S., Matsuda S., Kagamiishi Y., Tateishi N. Arundic acid (ONO-2506) ameliorates delayed ischemic brain damage by preventing astrocytic overproduction of S100B. Curr. Drug Targets CNS Neurol. Disord. 2005;4(2):127–142. [http://dx.doi. org/10.2174/1568007053544084]. [PMID: 15857298].
    1. Tateishi N., Mori T., Kagamiishi Y., Satoh S., Katsube N., Morikawa E., Morimoto T., Matsui T., Asano T. Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part II: suppression of astrocytic activation by a novel agent (R)-(-)-2-propyloctanoic acid (ONO-2506) leads to mitigation of delayed infarct expansion and early improvement of neurologic deficits. J. Cereb. Blood Flow Metab. 2002;22(6):723–734. []. [PMID: 12045671].
    1. Pettigrew L.C., Kasner S.E., Gorman M., Atkinson R.P., Funakoshi Y., Ishibashi H. Effect of arundic acid on serum S-100β in ischemic stroke. J. Neurol. Sci. 2006;251(1-2):57–61. [http:// ]. [PMID: 17092520].
    1. Simão F, Matté A, Matté C, Soares FMS, Wyse ATS, Netto CA. 2011.
    1. Canal C.C., Pagnussat A.S., Orlandi L., Worm P., Moura N., Etgen A.M. Coumestrol has neuroprotective effects before and after global cerebral ischemia in female rats. Brain Res. 2012;1474:82–90. [].
    1. Castro C.C., Pagnussat A.S., Moura N., da Cunha M.J., Machado F.R., Wyse A.T.S. Coumestrol treatment prevents Na+, K+-ATPase inhibition and affords histological neuroprotection to male rats receiving cerebral global ischemia. Neurol. Res. 2014;36(3):198–206.
    1. Cheng B., Christakos S., Mattson M.P. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron. 1994;12(1):139–153. [].
    1. Nicole O., Ali C., Docagne F., Plawinski L., MacKenzie E.T., Vivien D., Buisson A. Neuroprotection mediated by glial cell line-derived neurotrophic factor: involvement of a reduction of NMDA-induced calcium influx by the mitogen-activated protein kinase pathway. J. Neurosci. 2001;21(9):3024–3033. [http://dx. ]. [PMID: 11312287].
    1. Kilic U., Kilic E., Dietz G.P.H., Bähr M. Intravenous TAT-GDNF is protective after focal cerebral ischemia in mice. Stroke. 2003;34(5):1304–1310. [. 0000066869.45310.50]. [PMID: 12677018].
    1. Sumbria R.K., Boado R.J., Pardridge W.M. Combination stroke therapy in the mouse with blood–brain barrier penetrating IgG–GDNF and IgG–TNF decoy receptor fusion proteins. Brain Res. 2013;1507:91–96.
    1. Zhang Y., Pardridge W.M. Blood–brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion. Brain Res. 2006;1111(1):227–229. [ 10.1016/j.brainres.2006.07.005].
    1. Butovsky O., Ziv Y., Schwartz A., Landa G., Talpalar A.E. Pluchino, S Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 2006;31(1):149–160.
    1. Clausen B.H., Lundberg L., Yli-Karjanmaa M., Martin N.A., Svensson M., Alfsen M.Z. Fumarate decreases edema volume and improves functional outcome after experimental stroke. Exp. Neurol. 2017;295:144–154. [. 2017.06.011].
    1. Taylor R.A., Chang C-F., Goods B.A., Hammond M.D., Grory B.M., Ai Y. TGF-β1 modulates microglial phenotype and promotes re-covery after intracerebral hemorrhage. Clin. Investig. (Lond.) 2017;127(1):280–292.
    1. Dhungana H., Huuskonen M.T., Pihlajaniemi T., Heljasvaara R., Vivien D., Kanninen K.M., Malm T., Koistinaho J., Lemarchant S. Lack of collagen XV is protective after ischemic stroke in mice. Cell Death Dis. 2017;8(1):e2541. [ cddis.2016.456]. [PMID: 28079884].
    1. Mocco J., Choudhri T., Huang J., Harfeldt E., Efros L., Klingbeil C., Vexler V., Hall W., Zhang Y., Mack W., Popilskis S., Pinsky D.J., Connolly E.S., Jr HuEP5C7 as a humanized monoclonal anti-E/P-selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ. Res. 2002;91(10):907–914. [. 0000042063.15901.20]. [PMID: 12433835].
    1. Jin A.Y., Tuor U.I., Rushforth D., Kaur J., Muller R.N., Petterson J.L., Boutry S., Barber P.A. Reduced blood brain barrier breakdown in P-selectin deficient mice following transient ischemic stroke: a future therapeutic target for treatment of stroke. BMC Neurosci. 2010;11(1):12. []. [PMID: 20122276].
    1. Yago T., Petrich B.G., Zhang N., Liu Z., Shao B., Ginsberg M.H., McEver R.P. Blocking neutrophil integrin activation prevents ischemia-reperfusion injury. J. Exp. Med. 2015;212(8):1267–1281. []. [PMID: 26169939].
    1. Weise G., Pösel C., Möller K., Kranz A., Didwischus N., Boltze J. High-dosage granulocyte colony stimulating factor treatment alters monocyte trafficking to the brain after experimental stroke. Brain Behav. Immun. 2017;60:15–26. [. 2016.08.008].
    1. Sun Y., Jin K., Xie L., Childs J., Mao X.O., Logvinova A., Greenberg D.A. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J. Clin. Invest. 2003;111(12):1843–1851. []. [PMID: 12813020].
    1. Soleman S., Yip P.K., Duricki D.A., Moon L.D. Delayed treatment with chondroitinase ABC promotes sensorimotor recovery and plasticity after stroke in aged rats. Brain. 2012;135(Pt 4):1210–1223. []. [PMID: 22396394].
    1. Hill J.J., Jin K., Mao X.O., Xie L., Greenberg D.A. Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats. Proc. Natl. Acad. Sci. USA. 2012;109(23):9155–9160. [ pnas.1205697109]. [PMID: 22615373].
    1. Lee B., Clarke D., Al Ahmad A., Kahle M., Parham C., Auckland L., Shaw C., Fidanboylu M., Orr A.W., Ogunshola O., Fertala A., Thomas S.A., Bix G.J. Perlecan domain V is neuroprotective and proangiogenic following ischemic stroke in rodents. J. Clin. Invest. 2011;121(8):3005–3023. [ JCI46358]. [PMID: 21747167].
    1. Deroide N., Li X., Lerouet D., Van Vré E., Baker L., Harrison J., Poittevin M., Masters L., Nih L., Margaill I., Iwakura Y., Ryffel B., Pocard M., Tedgui A., Kubis N., Mallat Z. MFGE8 inhibits inflammasome-induced IL-1β production and limits postischemic cerebral injury. J. Clin. Invest. 2013;123(3):1176–1181. []. [PMID: 23454767].
    1. Zheng Y.Q., Liu J.X., Li X.Z., Xu L., Xu Y.G. RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats. Acta Pharmacol. Sin. 2009;30(7):919–927. []. [PMID: 19574998].
    1. Xu X., Chua K-W., Chua C.C., Liu C-F., Hamdy R.C., Chua B.H.L. Synergistic protective effects of humanin and necrostatin-1 on hypoxia and ischemia/reperfusion injury. Brain Res. 2010;1355:189–194.
    1. Chang P., Dong W., Zhang M., Wang Z., Wang Y., Wang T., Gao Y., Meng H., Luo B., Luo C., Chen X., Tao L. Anti-necroptosis chemical necrostatin-1 can also suppress apoptotic and autophagic pathway to exert neuroprotective effect in mice intracerebral hemorrhage model. J. Mol. Neurosci. 2014;52(2):242–249. []. [PMID: 24122153].
    1. Chen F., Su X., Lin Z., Lin Y., Yu L., Cai J. Necrostatin-1 attenuates early brain injury after subarachnoid hemorrhage in rats by inhibiting necroptosis. Neuropsychiatr. Dis. Treat. 2017;13:1771–1782. [].
    1. Lu W., Sun J., Yoon J.S., Zhang Y., Zheng L., Murphy E., Mattson M.P., Lenardo M.J. Mitochondrial protein PGAM5 regulates mitophagic protection against cell necroptosis. PLoS One. 2016;11(1):e0147792. [. 0147792]. [PMID: 26807733].
    1. Turlova E., Bae C.Y.J., Deurloo M., Chen W., Barszczyk A., Horgen F.D., Fleig A., Feng Z.P., Sun H.S. TRPM7 regulates axonal outgrowth and maturation of primary hippocampal neurons. Mol. Neurobiol. 2016;53(1):595–610. [ s12035-014-9032-y]. [PMID: 25502295].
    1. Sun H-S., Jackson M.F., Martin L.J., Jansen K., Teves L., Cui H. Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia. Nat. Neurosci. 2009;12(10):1300–1307. [].
    1. Chen W., Xu B., Xiao A., Liu L., Fang X., Liu R., Turlova E., Barszczyk A., Zhong X., Sun C.L., Britto L.R., Feng Z.P., Sun H.S. TRPM7 inhibitor carvacrol protects brain from neonatal hypoxic-ischemic injury. Mol. Brain. 2015;8(1):11. [http://dx.doi. org/10.1186/s13041-015-0102-5]. [PMID: 25761704].
    1. Lule S., Wu L., McAllister L.M., Edmiston W.J., Chung J.Y., Levy E. Genetic inhibition of receptor interacting protein kinase-1 reduces cell death and improves functional outcome after intracerebral hemorrhage in mice. 2017.
    1. Haugaard-Kedström L.M., Fernandes E.F.A., Strømgaard K. In: Targeting PSD-95 as a novel approach in the treatment of stroke. Neuroprotective Therapy for Stroke and Ischemic Disease; Lapchak, P.A. Zhang J.H., editor. Cham: Springer International Publishing; 2017. pp. 157–184. []
    1. Sun H-S., Doucette T.A., Liu Y., Fang Y., Teves L., Aarts M., Ryan C.L., Bernard P.B., Lau A., Forder J.P., Salter M.W., Wang Y.T., Tasker R.A., Tymianski M. Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke. 2008;39(9):2544–2553. [ STROKEAHA.107.506048]. [PMID: 18617669].
    1. Xu B., Xiao A-J., Chen W., Turlova E., Liu R., Barszczyk A., Sun C.L.F., Liu L., Tymianski M., Feng Z.P., Sun H.S. Neuroprotective effects of a PSD-95 inhibitor in neonatal hypoxic-Ischemic brain injury. Mol. Neurobiol. 2016;53(9):5962–5970. []. [PMID: 26520452].
    1. Stary C.M., Xu L., Li L., Sun X., Ouyang Y-B., Xiong X. Inhibition of miR-181a protects female mice from transient focal cerebral ischemia by targeting astrocyte estrogen receptor-α. Mol. Cell. Neurosci. 2017;82:118–125. [. 2017.05.004].
    1. Xu L-J., Ouyang Y-B., Xiong X., Stary C.M., Giffard R.G. Post-stroke treatment with miR-181 antagomir reduces injury and improves long-term behavioral recovery in mice after focal cerebral ischemia. Exp. Neurol. 2015;264:1–7. [. 1016/j.expneurol.2014.11.007].
    1. Mo J-L., Liu Q., Kou Z-W., Wu K-W., Yang P., Chen X-H., Sun F.Y. MicroRNA-365 modulates astrocyte conversion into neuron in adult rat brain after stroke by targeting Pax6. Glia. 2018;66(7):1346–1362. []. [PMID: 29451327].
    1. Wang X., Chen S., Ni J., Cheng J., Jia J., Zhen X. miRNA-3473b contributes to neuroinflammation following cerebral ischemia. Cell Death Dis. 2018;9(1):11.
    1. Yang X., Tang X., Sun P., Shi Y., Liu K., Hassan S.H., Stetler R.A., Chen J., Yin K.J. MicroRNA-15a/16-1 Antagomir ameliorates ischemic brain injury in experimental stroke. Stroke. 2017;48(7):1941–1947. [. 017284]. [PMID: 28546328].
    1. Zhao F., Qu Y., Zhu J., Zhang L., Huang L., Liu H., Li S., Mu D. miR-30d-5p plays an important role in autophagy and apoptosis in developing rat brains after hypoxic-ischemic injury. J. Neuropathol. Exp. Neurol. 2017;76(8):709–719. [. 1093/jnen/nlx052]. [PMID: 28789480].
    1. Kokaia Z., Tornero D., Lindvall O. Transplantation of reprogrammed neurons for improved recovery after stroke. 2017.
    1. Li Y., Chen J., Zhang C.L., Wang L., Lu D., Katakowski M., Gao Q., Shen L.H., Zhang J., Lu M., Chopp M. Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia. 2005;49(3):407–417. [. 1002/glia.20126]. [PMID: 15540231].
    1. Shen L.H., Li Y., Chen J., Zacharek A., Gao Q., Kapke A., Lu M., Raginski K., Vanguri P., Smith A., Chopp M. Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J. Cereb. Blood Flow Metab. 2007;27(1):6–13. [http://dx. ]. [PMID: 16596121].
    1. Bang O.Y., Lee J.S., Lee P.H., Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann. Neurol. 2005;57(6):874–882. []. [PMID: 15929052].
    1. Shen L.H. Li.; Chen, J.; Zhang, J.; Vanguri, P.; Borneman, J. Intracarotid transplantation of bone marrow stromal cells increases axon-myelin remodeling after stroke. Neuroscience. 2006;137(2):393–399. [].
    1. Hara K., Matsukawa N., Yasuhara T., Xu L., Yu G., Maki M., Kawase T., Hess D.C., Kim S.U., Borlongan C.V. Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke: in vitro evidence of expedited neuronal differentiation and GDNF secretion. J. Neurosci. Res. 2007;85(6):1240–1251. [http://dx.doi. org/10.1002/jnr.21234]. [PMID: 17335085].
    1. Hara K., Yasuhara T., Maki M., Matsukawa N., Masuda T., Yu S.J. Neural progenitor NT2N cell lines from teratocarcinoma for transplantation therapy in stroke. Prog. Neurobiol. 2008;85(3):318–334.
    1. Banerjee S., Bentley P., Hamady M., Marley S., Davis J., Shlebak A., Nicholls J., Williamson D.A., Jensen S.L., Gordon M., Habib N., Chataway J. Intra-arterial immunoselected CD34+ stem cells for acute Ischemic Stroke. Stem Cells Transl. Med. 2014;3(11):1322–1330. []. [PMID: 25107583].
    1. Jin W-N, Shi SX-Y, Li Z, Li M, Wood K, Gonzales R.J. Depletion of microglia exacerbates postischemic inflammation and brain injury. 2017.
    1. Majmundar N., Kim B., Prestigiacomo C.J. Necroptosis pathway in treatment of intracerebral hemorrhage: Novel therapeutic target. World Neurosurg. 2016;89:716–717. [. 1016/j.wneu.2016.03.071]. [PMID: 27020976].
    1. Gao L., Dong Q., Song Z., Shen F., Shi J., Li Y. NLRP3 inflammasome: a promising target in ischemic stroke. Inflamm. Res. 2017;66(1):17–24. []. [PMID: 27576327].
    1. Underly R.G., Levy M., Hartmann D.A., Grant R.I., Watson A.N., Shih A.Y. Pericytes as Inducers of Rapid, Matrix Metalloproteinase-9-Dependent Capillary Damage during Ischemia. J. Neurosci. 2017;37(1):129–140. [ JNEUROSCI.2891-16.2016]. [PMID: 28053036].
    1. Siniscalchi A., Iannacchero R., Anticoli S., Pezzella F.R., De Sarro G., Gallelli L. Anti-inflammatory strategies in stroke: a potential therapeutic target. Curr. Vasc. Pharmacol. 2016;14(1):98–105. []. [PMID: 26411421].
    1. Suzuki H., Hayashi T., Tojo S.J., Kitagawa H., Kimura K., Mizugaki M., Itoyama Y., Abe K. Anti-P-selectin antibody attenuates rat brain ischemic injury. Neurosci. Lett. 1999;265(3):163–166. []. [PMID: 10327156].
    1. Suzuki H., Abe K., Tojo S.J., Kitagawa H., Kimura K., Mizugaki M., Itoyama Y. Reduction of ischemic brain injury by anti-P-selectin monoclonal antibody after permanent middle cerebral artery occlusion in rat. Neurol. Res. 1999;21(3):269–276. [http:// ]. [PMID: 10319335].
    1. Ouyang Y.B., Stary C.M., Yang G.Y., Giffard R. microRNAs: innovative targets for cerebral ischemia and stroke. Curr. Drug Targets. 2013;14(1):90–101. [ 138945013804806424]. [PMID: 23170800].
    1. Gallelli L., Siniscalchi A., Carotenuto M., Caroleo M.C., Cione E., Guidetti V. microRNAs-based predictor factor in patients with migraine-ischemic stroke. MicroRNA. 2017;6(1):17–21. [http:// ]. [PMID: 28056747].
    1. Ren C., Han R., Shi J., Ji X. In: Ischemic stroke pathophysiology and cell therapy.Bone marrow stem cell therapy for stroke; Jin, K.; Ji, X.; Zhuge, Q. Singapore S., editor. Singapore: 2017. pp. 1–36. []
    1. Azad T.D., Veeravagu A., Steinberg G.K. Neurorestoration after stroke. Neurosurg. Focus. 2016;40(5):E2. [. 3171/2016.2.FOCUS15637]. [PMID: 27132523].
    1. Albers G.W., Goldstein L.B., Hess D.C., Wechsler L.R., Furie K.L., Gorelick P.B., Hurn P., Liebeskind D.S., Nogueira R.G., Saver J.L. 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. []. [PMID: 21852620].

Source: PubMed

3
Suscribir