Table of Contents

    Topic review

    Ischemic Stroke

    Subjects: Pathology
    View times: 192


    "The term stroke is defined as ”…a neurological deficit attributed to an acute focal injury of the central nervous system (CNS) by a vascular cause, including cerebral infarction, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH)…”, thus comprising an intraluminal obstructive/ischemic and/or wall tear and a lesion mechanism.

    1. Introduction

    Generally, although with nuances mostly depending on the period when a specific study was undertaken, the geographic area examined, and the research methodology applied, a completed stroke is the most prevalent among major neurological conditions[1] and is the second-leading cause of death worldwide[2]. It has a marked potential to generate residual disability[3]; more precisely, “…almost two-thirds of stroke survivors leave hospital with a disability”[4]. These disabilities are quite often severe and/or permanent and account for the largest proportion of total disability-adjusted life years (DALYs), as the “largest contributor to this burden globally”[5], with a consequent socioeconomic impact[6], thus highlighting the severity of the overall impact of strokes. Strokes mainly affect the elderly, but “…approximately 10% of strokes occur in patients below 50 years of age”[7]. The increasing frequency of this condition in younger people represents a divergent trend from its global incidence and mortality, which seem to be diminishing[3][6][7].

    “More women than men suffer strokes due to the risks of pregnancy, childbirth, and oral contraceptive use before age 30”[7]. Specifically, due to these risks, 从prevails in younger patients and in elderly women, whereas it is more frequent in adult men, until reaching advanced (over 65 years—o.n.) age[8].

    The total number of stroke events in the European Union (EU) was 613,148 in 2015 and is estimated to increase to 819,771 in 2035[9], although the incidence and consequent mortality of strokes have had a descending trend since the early 2000s. Considerable differences exist between Eastern and Western Europe concerning the burden of stroke, which is significantly higher in Eastern European countries, including in terms of the specific mortality, which depends on better and faster treatment. This connects to the overall performance of each health care system, which is in turn linked with its level of financing, as well as with the effectiveness of public education campaigns to encourage an emergency response to stroke[9]. Romania ranks first among EU countries in both stroke incidence and mortality[9].

    "Stroke is one of the largest problems and clinical-social challenges within neurology and, in general, pathology. This entry briefly reviewed the main pathophysiological mechanisms of ischemic stroke – which represent, at the same time, targets for medical interventions – including those, identified by modern related knowledge, that can be counteracted, at least partially, by a calf blood deproteinized hemodialysate/ultrafiltrate medicine (Actovegin®)". 

    2. The Main Pathophysiological Mechanism

    Regarding the main pathophysiological mechanisms of ischemic stroke targeted in this study, as preliminary considerations, preformed tissues for specific excitability, such as neurons, and most glial and striated muscle cells do not reproduce or replicate after a person is born[10][11]. Under injury conditions (e.g., ischemia in stroke), the central nervous system (CNS) reacts through preformatted pathways, which, for yet unknown reasons, exert active opposition to axonal regrowth and brakes to self-recovery within detrimental evolutive pathways[12].

    A CNS insult entails, conditioned by complex, particular and not yet sufficiently deciphered mechanisms, a succession of local and regional damages. However, these damages have wide impacts from the intimate and genic on the body’s ensemble and systemic levels, which are classified as primary and secondary (events cascade) lesions[12][13][14][15][16]. Eventually, in total, the primary and secondary lesions contribute to neurological impairment[15].

    Some lesion secondary developments overlap and are common for CNS conditions of different causes and partially comprise related biological pathways[17]. “Therefore, the concept of secondary CNS (including brain) injuries has become, especially in the last decades, the basis for developing an array of neuroprotective modern therapies in traumatic, ischemic, and degenerative injuries of the CNS (including both the brain and the spinal cord)”[13]. Thus, the drastic reduction of the cerebral blood flow by a sudden obstruction of predominantly large extracranial (vertebral/basilar, mostly internal, carotid) and/or intracranial (supplying or emerging from the Circle of Willis) arteries or small vessel(s) exposes the brain, the most dependent organ on oxygen metabolic consumption, to ischemia and deprivation of glucose provision. The latter appears to lower the brain tissue resistance to hypoxia; if such a severe interruption lasts more than five minutes without enough flux compensation through collateral circulation variants, it results in irreversible damage and consequent large brain infarction[18][19][20][21]. The occlusion is caused in most cases by thrombosis/thrombus formation in the atherosclerotic plaques (prominent in the vascular lumen(s)), which characterizes atherosclerotic cerebrovascular disease, microatheroma, lipohyalinosis (related to small, deep vessel thromboses, resulting more often in cerebral lacunar infarct lesions), embolism, hemodynamic severe disturbance leading to cerebral hypoperfusion, or, in rarer cases, local inflammatory conditions, like vasculitis[18][21][22]. The atherosclerotic lesions of the vascular walls are also considered to be of inflammatory origin: leukocyte local infiltration, proinflammatory cytokines, and adhesion molecule release, which favor monocyte and T-lymphocyte endothelial adherence and lead to subsequent penetration and maintenance of a continuous inflammatory status[21][23] and/or a systemically infectious origin (Chlamydia pneumoniae, Cytomegalovirus, and Helicobacter pylori)[23]. Consequently, after blood supply arrest, a succession of extremely complex and intertwined pathophysiological processes begins within seconds[8], both detrimental and as part of the recovery, which may continue for weeks, months, or years, until reaching a clinical-evolutive relative plateau[24]. These processes are emphasized briefly below.

    Abrupt and relatively prolonged deprivation of blood flow, i.e., oxygen and energetic (basically, glucose) support, leads to production collapse and drastic shortage, especially of the metabolically produced principal molecular storage and energy provider, ATP, in the most-affected brain tissue. Such severe biochemical injury generates an important amount of direct necrotic cell deaths in the core of the ischemic zone, in part because the membranes’ functional and structural integrity can no longer be sustained. Being energy-dependent, resting and excitation neuronal states, which are both membrane-active processes, are markedly altered, resulting in local still-living cells dying or being at increased risk of dying (although this may be remedied if irrigation is restored sufficiently quickly). This collateral perfusion occurs in the ischemic penumbra of the infarct’s periphery: (1) in neural control disturbance/abolishment of various types and severities and over different directly and/or indirectly connected territories and (2) in enhanced, inappropriate, and detrimental inner bio-pathologic augmented activity with enhanced ATP consumption, which is already diminished[8][17][25].

    If the blood flow arrest continues without sufficient collateral flux supply and within cerebrovascular autoregulation[20] or in the peripherally situated ischemic penumbra, further injuries may occur, including, at the intimate level, disturbance of mitochondrial functionality with a consequently imbalanced ratio between pro- and antioxidant factors (including related scavengers) in favor of the former). Oxidative (or nitrosative) stress is mainly generated by the highly enhanced production of reactive oxygen species (ROS), generally associated with depletion but with time-dependent sequential nuances, instead providing a gene-coded transcription-factor-mediated activation of an endogenous-related defense capability. The antioxidant-response elements (AREs) of antioxidants, such as l-c-γ-glutamyl-l-cysteinylglycine (glutathione (GSH)), are highly important[26][32][28][29][30][32][32]. Subsequently, lipid peroxidation, together with phospholipases, also affect the membranes’ integrity. Other critical damage actions of ROS include augmentation of the Ca2+ intracellular amount, cytoskeleton, and DNA insults with protein oxidation[33][34], proclivity to secondary misfolding[17], enhanced involvement by gene expression activation of nuclear factor-κβ (NF-κB) of proinflammatory cytokines (chemokines and interleukins) and adhesion molecules (expressed by activated endothelial cells, which attract and stimulate the tissue plasminogen activator (t-PA) and are also considered to have therapeutic capabilities, as recombinant tissue plasminogen activator; rtPA)[35][36], and the stimulation of matrix metalloproteinases (MMPs) and other (metallo) proteases[20][37].

    First, soon after ischemia is installed, neutrophils infiltrate (chemotactism) and injure the blood–brain barrier (BBB). A modern, expanded, more complex, and related conceptual structuring is the neurovascular unit that physiologically entails, by cell–cell signaling and interactions, the coordinated and efficacious comprehension and functioning of the BBB location, neurons, microglia, astrocytes, pericytes, endothelial smooth muscle cells, and intrinsic matrix proteins, and which has the adaptive capability to dynamically modify itself according to and within morphological-functional changes during post-stroke partial recovery[39][39]. Subsequently, macrophages and lymphocytes, including T cytotoxic (natural killer; NK) and B types[34], enter the damaged cerebral tissue within the above-mentioned inflammation context. In addition to those already noted, the related primum movens dwells in the signals represented by the modified osmolarity[40] and consistency of the slack post-occlusion blood, addressed to the local endothelial structure and thrombocytes[35]. Additionally involved in different but interlinked pathophysiological-related sequences are leukotrienes; growth factors; prostaglandins; astrocytes; further cell adhesion molecules, e.g., selectins; intercellular adhesion molecule 1 (ICAM-1); vascular cell adhesion molecule 1 (VCAM-1); and integrins[8][15][20][34], including with and through microglial cells that are resident in the CNS and partially transformed into phagocytes[35]. Different inflammatory pathways, some of which are respiratory[17], are also stimulated by accumulation of necrotic debris in the focal ischemic zone[37][41].

    Consequent to hypoxia, the complex pathophysiological context of the ischemic stroke partially and briefly outlined above also entails acidosis, which is metabolically induced in local hypo- or anoxic circumstances, with the accumulation of lactate and hydrogen ions (H+); the latter stimulates the production of ferrous iron-mediated ROS[8][25][34][36]. The major pathways for cell deaths are apoptosis (type I) and apoptosis-like/anoikis, autophagy (type II), and necrosis (type III)[17][39][42].

    ”Brain infarction was traditionally considered to be a classic example of liquefactive necrosis”[43] that can supervene quickly and brutally within a few minutes after severe and prolonged brain ischemia in the cerebral tissue, which has low tolerance to hypoxemia, such that necrosis is prone to be augmented by further pathophysiological mechanisms[44] via osmolar overload and consequent osmolysis, especially if suddenly installed[17][40]. However, a similar irreversible outcome, i.e., cell death, may also result following the other linked pathophysiological secondary injury events (summarized above) but more slowly. These latter delayed deadly damages nonetheless offer a time window for the at-risk biological structures to be rescued, at least partially[8], by spontaneous processes (prompt reperfusion, mainly based on efficient collateral blood supply restoration and vessel repermeabilization) and/or interventions. Within a major ischemic stroke, except for the overall successfully achieved (rtPA) thrombolysis, such favorable inner natural evolutions or outcomes usually do not prevail. Thereby, apoptosis and apoptosis-like phenomena also occur, including concomitantly. The former, apoptosis, is the classic pattern of programmed cell death. It often entails the mediated destruction of caspases via its propensity for phagocytosis cells to break up in connection with nuclear condensation. This may run on the intrinsic[8][27][43] mitochondrial pathway based on the release signaling of cytochrome c (a key component in the respiratory chain) and endonuclease G by proteins such as Bad, Bak, Bax, Bid, and Bim and/or those involved in metabolic pathway regulation and membrane lipids. Apoptosis may also involve permeability transition pore openings in the inner membrane components that mainly contribute to the mitochondrial outer membranes permeabilization (MOMP)[34][43][45][46]. Apoptosis targets connected enzymes such as poly-ADP-ribose-polymerase (PARP), which is, with important sex differences in its effects and with consequent nuclear DNA damage and/or exit from the mitochondria, entrance into the intracellular fluid, and continued translocation into the nucleus of the apoptosis-inducing factor (AIF), considered as being caspase-independent[34][47].

    The extrinsic pathway is initiated by suicidal molecular signals such as lethal ligands or death ligand trimer, responsible for the ligation to the cell external surface of death receptors, for tumor necrosis factor (TNF)-related apoptosis-inducing ligands (TRAIL), such as tumor necrosis factor α (TNF-α), the human diploid fibroblast (FS-7) cell-line-associated surface antigen, (Fas)/Apoptosis antigen, Apo-1 (Cluster of Differentiation (CD95)), and death receptor 4 (DR4)[8][34][47][48][49][50]. Eventually, all these pathophysiological mechanisms lead to cellular dysfunction. Apoptosis and apoptosis-like forms are relatively different concerning the related changes in the nuclear structure: apoptosis involves “…stage II chromatin condensation into compact figures…”, whereas apoptosis-like involves “…less-compact chromatin condensation” (stage I)[45].

    An additional pathway, named anoikis, involves the detachment of cells from the extracellular matrix (ECM)[51], including mainly with “…MMP-induced proteolysis of the neurovascular matrix …”[39]. This may also lead to programed cell death soon after stroke onset, consequent to the BBB deterioration. Specifically, this occurs due to the neurovascular unit’s morphological impairment, and its secondary disfunction regards the signaling of the related inter-cells with their ECM[17][39].

    Notably, in brain ischemia, necrosis, and different types of apoptosis/programed cell death, the same neuron may be affected simultaneously by caspases, calpains, and cathepsins[43]."

    The entry is from 10.3390/ijms21093181


    1. B. K. Macdonald; O. C. Cockerell; Josemir W. Sander; S. D. Shorvon; The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK.. Brain 2000, 123, 665-676, 10.1093/brain/123.4.665.
    2. Boden-Albala, B.; Appleton, N.; Schram, B. Stroke Epidemiology and Prevention (Chapter 1). In Stroke Rehabilitation; Wilson, R., Raghavan, P., Eds.; Elsevier: St. Louis, MO, USA, 2019.
    3. B. K. Macdonald; O. C. Cockerell; Josemir W. Sander; S. D. Shorvon; The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK.. Brain 2000, 123, 665-676, 10.1093/brain/123.4.665.
    4. Valery Feigin; Mohammad H Forouzanfar; Rita Krishnamurthi; George A Mensah; Myles Connor; Derrick A Bennett; Andrew E Moran; Ralph L Sacco; Laurie Anderson; Thomas Truelsen; et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010.. The Lancet 2014, 383, 245-54, 10.1016/s0140-6736(13)61953-4.
    5. Ropper, A.H.; Samuels, M.A.; Klein, J.P. Cerebrovascular Diseases (Chapter 34). In Adams and Victor’s: Principles of Neurology, 10th ed.; Mc Graw Hill Education: Boston, MA, USA, 2014; p. 781.
    6. Sara L. Pulit; Lu-Chen Weng; Patrick F. McArdle; Ludovic Trinquart; Seung Hoan Choi; Braxton D. Mitchell; Jonathan Rosand; Paul I. W. De Bakker; Emelia J. Benjamin; Patrick T. Ellinor; et al. Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes. Neurology Genetics 2018, 4, e293, 10.1212/nxg.0000000000000293.
    7. Valery Feigin; Amanuel Alemu Abajobir; Kalkidan Hassen Abate; Foad Abd-Allah; Abdishakur M Abdulle; Semaw Ferede Abera; Gebre Yitayih Abyu; Muktar Ahmed; Amani Nidhal Aichour; Ibtihel Aichour; et al. Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet Neurology 2017, 16, 877-897, 10.1016/S1474-4422(17)30299-5.
    8. Christopher A. Stack; John Cole; Ischemic stroke in young adults. Current Opinion in Cardiology 2018, 33, 594-604, 10.1097/hco.0000000000000564.
    9. Frontera, W.R.; Silver, J.; Rizzo, T. Stroke in Young Adults. In Essentials of Physical Medicine and Rehabilitation: Musculoskeletal Disorders, Pain and Rehabilitation, 4th ed.; Elsevier: St. Louis, MO, USA, 2018; p. 937.
    10. Kanyal, N.; The science of ischemic stroke: pathophysiology & pharmacological treatment. nt. J. Pharm. Sci. Rev. Res. 2015, 4, 65–84, .
    11. Stevens, E.; Emmett, E.; Wang, Y.; McKevitt, W.C.; Wolfe, C. The Burden of Stroke in Europe. The Challenge for Policy Makers—King’s College London for the Stroke Alliance for Europe (SAFE), 2017. Available online: (accessed on 29 April 2020).
    12. L. Manuelidis; Different central nervous system cell types display distinct and nonrandom arrangements of satellite DNA sequences.. Proceedings of the National Academy of Sciences 1984, 81, 3123-3127, 10.1073/pnas.81.10.3123.
    13. Hall, J.E.; Guyton, A.C. . Genetic Control of Protein Synthesis, Cell Function, and Cell Reproduction; Saunders Elsevier: Philadelphia, PA, USA, 2011; pp. 39.
    14. G Onose; M Haras; D Mureşanu; C Giuglea; D Chendreanu; Integrative emphases on intimate, intrinsic propensity/ pathological processes–causes of self recovery limits and also, subtle related targets for neuroprotection/ pleiotropicity/ multimodal actions, by accessible therapeutic approaches–in spinal cord injuries. Journal of Medicine and Life 2010, 3, 262-274, .
    15. G Onose; Cristina Daia; B Haras; Tiberiu Spircu; Aurelian Anghelescu; Ciurea; Anca Sanda Mihaescu; Liliana Onose; A long-term, complex, unitary appraisal regarding neurorestorative, including neurorehabilitative, outcomes in patients treated with Cerebrolysin®, following traumatic brain injury. Journal of Neurorestoratology 2014, 2, 85, 10.2147/jn.s49693.
    16. Yi Ren; Xiang Zhou; Xijing He; Function of microglia and macrophages in secondary damage after spinal cord injury. Neural Regeneration Research 2014, 9, 1787-1795, 10.4103/1673-5374.143423.
    17. David J. Loane; Alan I. Faden; Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends in Pharmacological Sciences 2010, 31, 596-604, 10.1016/
    18. G Onose; A Anghelescu; D F Muresanu; L Padure; M A Haras; C O Chendreanu; L V Onose; A Mirea; A V Ciurea; W S El Masri; et al. A review of published reports on neuroprotection in spinal cord injury. Spinal Cord 2009, 47, 716-726, 10.1038/sc.2009.52.
    19. Muresanu, D.F.; Radulescu, A.; Marginean, M.; Toldisan, I.; Neuroprotection and Neuroplasticity in Traumatic Brain Injury. SNPCAR 2007, 10, 3–8, .
    20. Frontera, W.R.; DeLisa, J.A.; Gans, B.M.; Robinson, L.R.; Bockeneck, W.; Chase, J. Stroke Rehabilitation (Chapter 18). In DeLisa’s Physical Medicine & Rehabilitation. Principles and Practice, 6th ed.; Wolters Kluwer: Philadelphia, PA, USA, 2019; pp. 356–357.
    21. Cifu, D.X. Stroke Syndromes (Chapter 44). In Braddom’s Physical Medicine and Rehabilitation, 5th ed.; Elsevier: Philadelphia, PA, USA, 2016; p. 1001.
    22. J Q Jin; W Li; Y L Mu; Y Jiang; Y X Zhang; Z Y Lu; [Study on the oral mucosal diseases in patients with cerebrovascular diseases].. Chin. J. Epidemiol. 2019, 40, 1003-1005, .
    23. Braddom, R.L. Physical Medicine & Rehabilitation, 3rd ed.; Elsevier: Philadephia, PA, USA, 2007; pp. 1176–1177.
    24. Stefanie Schreiber; Annette Wilisch‐Neumann; Anne Assmann; Vincent Scheumann; Valentina Perosa; Solveig Jandke; Christian Mawrin; Roxana O Carare; David J. Werring; Frank Schreiber; et al. Invited Review: The spectrum of age‐related small vessel diseases: potential overlap and interactions of amyloid and nonamyloid vasculopathies. Neuropathology and Applied Neurobiology 2019, null, null, 10.1111/nan.12576.
    25. Andrea Rognoni; Chiara Cavallino; Alessia Veia; Sara Bacchini; Roberta Rosso; Manuela Facchini; Gioel G Secco; Alessandro Lupi; Federico Nardi; Francesco Rametta; et al. Pathophysiology of Atherosclerotic Plaque Development.. Cardiovascular & Hematological Agents in Medicinal Chemistry 2015, 13, 10-13, 10.2174/1871525713666141218163425.
    26. Julie Bernhardt; Kathryn S. Hayward; Gert Kwakkel; Nick S Ward; Steven L Wolf; Karen N. Borschmann; John W Krakauer; Lara A. Boyd; S. Thomas Carmichael; Dale Corbett; et al. Agreed definitions and a shared vision for new standards in stroke recovery research: The Stroke Recovery and Rehabilitation Roundtable taskforce. International Journal of Stroke 2017, 12, 444-450, 10.1177/1747493017711816.
    27. Changhong Xing; Ken Arai; Eng H. Lo; Marc Hommel; Pathophysiologic cascades in ischemic stroke.. International Journal of Stroke 2012, 7, 378-85, 10.1111/j.1747-4949.2012.00839.x.
    28. Howard Prentice; Jigar Pravinchandra Modi; Jang-Yen Wu; Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases. Oxidative Medicine and Cellular Longevity 2015, 2015, 1-7, 10.1155/2015/964518.
    29. Ramón, R.; García, J.C. Excitotoxicity and Oxidative Stress in Acute Stroke. In Ischemic Stroke—Updates; IntechOpen Limited: London, UK, 2016.
    30. Lei Liu; Logan M. Locascio; Sylvain Doré; Critical Role of Nrf2 in Experimental Ischemic Stroke.. Frontiers in Pharmacology 2019, 10, 153, 10.3389/fphar.2019.00153.
    31. Kenji Namba; Yoshimasa Takeda; Kazuharu Sunami; Masahisa Hirakawa; Temporal Profiles of the Levels of Endogenous Antioxidants After Four-Vessel Occlusion in Rats. Journal of Neurosurgical Anesthesiology 2001, 13, 131-137, 10.1097/00008506-200104000-00010.
    32. Juhyun Song; Joohyun Park; Yumi Oh; Jong Eun Lee; Glutathione Suppresses Cerebral Infarct Volume and Cell Death after Ischemic Injury: Involvement of FOXO3 Inactivation and Bcl2 Expression. Oxidative Medicine and Cellular Longevity 2015, 2015, 1-11, 10.1155/2015/426069.
    33. Ming-Shuo Sun; Hang Jin; Xin Sun; Shuo Huang; Fu-Liang Zhang; Zhen-Ni Guo; Yi Yang; Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy. Oxidative Medicine and Cellular Longevity 2018, 2018, 1-17, 10.1155/2018/3804979.
    34. Haddad, J.J.; Harb, H.L. L-gamma-Glutamyl-L-cysteinyl-glycine (glutathione; GSH) and GSH-related enzymes in the regulation of pro- and anti-inflammatory cytokines: A signaling transcriptional scenario for redox(y) immunologic sensor(s). Mol. Immunol. 2005, 42, 987–1014.
    35. Christine You-Jin Bae; Hong-Shuo Sun; TRPM7 in cerebral ischemia and potential target for drug development in stroke. Acta Pharmacologica Sinica 2011, 32, 725-733, 10.1038/aps.2011.60.
    36. Seyed Esmaeil Khoshnam; William Winlow; Maryam Farzaneh; Yaghoob Farbood; Hadi Fathi Moghaddam; Pathogenic mechanisms following ischemic stroke. Neurological Sciences 2017, 38, 1167-1186, 10.1007/s10072-017-2938-1.
    37. Josef Anrather; Costantino Iadecola; Inflammation and Stroke: An Overview. Neurotherapeutics 2016, 13, 661-670, 10.1007/s13311-016-0483-x.
    38. Io Onwuekwe; B Ezeala-Adikaibe; Ischemic Stroke and Neuroprotection. Annals of Medical and Health Sciences Research 2012, 2, 186-190, 10.4103/2141-9248.105669.
    39. Ramón Rodrigo; Rodrigo Fernández-Gajardo; Rodrigo Gutiérrez; José Manuel Matamala; Rodrigo Carrasco; Andrés Miranda-Merchak; Walter Feuerhake; Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities.. CNS & Neurological Disorders - Drug Targets 2013, 12, 698-714, 10.2174/1871527311312050015.
    40. Andrews, A.M.; Gerhardt, G.A.; Daws, L.C.; Shoaib, M.; Mason, B.J.; Heyser, C.J.; De Lecea, L.; Balster, R.L.; Walsh, S.; Dahmen, M.M.; et al. Neurovascular Unit. In Encyclopedia of Psychopharmacology; Springer-Verlag GmbH: Heidelberg, Germany, 2010; p. 877.
    41. Ken Arai; Josephine Lok; Shuzhen Guo; Kazuhide Hayakawa; Changhong Xing; Eng H. Lo; Cellular mechanisms of neurovascular damage and repair after stroke.. Journal of Child Neurology 2011, 26, 1193-8, 10.1177/0883073811408610.
    42. Ropper, A.; Samuels, M. Intracranial Neoplasms and Parneoplastic Disorders (Chapter 31)—Brain Edema. In Adams and Victor’s Principles of Neurology, 9th ed.; McGraw-Hill Professional: New York City, NY, USA, 2009; pp. 618–619.
    43. Jong Youl Kim; Joohyun Park; Ji Young Chang; Sa-Hyun Kim; Jong Eun Lee; Inflammation after Ischemic Stroke: The Role of Leukocytes and Glial Cells. Experimental Neurobiology 2016, 25, 241-251, 10.5607/en.2016.25.5.241.
    44. Ai-Ping Qin; Hui-Ling Zhang; Zheng-Hong Qin; Mechanisms of lysosomal proteases participating in cerebral ischemia-induced neuronal death. Neuroscience Bulletin 2008, 24, 117-123, 10.1007/s12264-008-0117-3.
    45. Isın Ünal-Çevik; Munire Kılınç; Alp Can; Yasemin Gürsoy-Ozdemir; Turgay Dalkara; Apoptotic and Necrotic Death Mechanisms Are Concomitantly Activated in the Same Cell After Cerebral Ischemia. Stroke 2004, 35, 2189-2194, 10.1161/01.str.0000136149.81831.c5.
    46. Mureşanu, D.F. Neuromodulation with Pleiotropic and Multimodal Drugs—Future Approaches to Treatment of Neurological Disorders. In Brain Edema XIV. Acta Neurochirurgica Supplementum; Springer: Vienna, Austria, 2010; Volume 106, pp. 291–294.
    47. Linda E. Bröker; Frank A. E. Kruyt; Giuseppe Giaccone; Cell Death Independent of Caspases: A Review. Clinical Cancer Research 2005, 11, 3155-3162, 10.1158/1078-0432.ccr-04-2223.
    48. Douglas R. Green; Guido Kroemer; The Pathophysiology of Mitochondrial Cell Death. Science 2004, 305, 626-629, 10.1126/science.1099320.
    49. Jesse T Lang; Louise D. McCullough; Pathways to ischemic neuronal cell death: are sex differences relevant?. Journal of Translational Medicine 2008, 6, 33-33, 10.1186/1479-5876-6-33.
    50. Medical & Biological Laboratories (MBL). Life Science. Available online: (accessed on 28 April 2020).
    51. Shigekazu Nagata; Early work on the function of CD95, an interview with Shige Nagata. Cell Death & Differentiation 2004, 11, S23-S27, 10.1038/sj.cdd.4401453.