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Neural Plasticity
Volume 2019, Article ID 9708905, 10 pages
https://doi.org/10.1155/2019/9708905
Review Article

Brain Functional Reserve in the Context of Neuroplasticity after Stroke

1Department of Applied Physiology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland
2Department Neurology, Central Clinical Hospital of the Ministry of the Interior and Administration, Wołoska 137, 02-507 Warsaw, Poland
3Department of Public Health, 2nd Faculty of Medicine, Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland
4Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
5Department of Neurosurgery, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, W. K. Roentgena 5, 02-781 Warsaw, Poland
6Department of Information Technology and Medical Statistics, Faculty of Health Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland
7Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland

Correspondence should be addressed to Jan Dąbrowski; lp.nap.kidmi@badnaj

Received 8 November 2018; Accepted 3 January 2019; Published 27 February 2019

Guest Editor: Matthew Zabel

Copyright © 2019 Jan Dąbrowski et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Stroke is the second cause of death and more importantly first cause of disability in people over 40 years of age. Current therapeutic management of ischemic stroke does not provide fully satisfactory outcomes. Stroke management has significantly changed since the time when there were opened modern stroke units with early motor and speech rehabilitation in hospitals. In recent decades, researchers searched for biomarkers of ischemic stroke and neuroplasticity in order to determine effective diagnostics, prognostic assessment, and therapy. Complex background of events following ischemic episode hinders successful design of effective therapeutic strategies. So far, studies have proven that regeneration after stroke and recovery of lost functions may be assigned to neuronal plasticity understood as ability of brain to reorganize and rebuild as an effect of changed environmental conditions. As many neuronal processes influencing neuroplasticity depend on expression of particular genes and genetic diversity possibly influencing its effectiveness, knowledge on their mechanisms is necessary to understand this process. Epigenetic mechanisms occurring after stroke was briefly discussed in this paper including several mechanisms such as synaptic plasticity; neuro-, glio-, and angiogenesis processes; and growth of axon.

1. Introduction

According to the new definition of stroke by the AHA/ASA from 2013, it includes any objective evidence of permanent brain, spinal cord, or retinal cell death due to a vascular cause [1]. In clinical terms, stroke is diagnosed when neurologic deficit in a form of speech, visual disturbance, muscle weakness, or cerebellar dysfunction lasts more than 24 h. In case of symptoms lasting for a shorter period of time, transient ischemic attack (TIA) is diagnosed provided without focus of ischemia in neuroimaging exams [2]. Terms utilizing duration of neurologic symptoms are currently being redefined with use of high-tech imaging methods such as magnetic resonance imaging (MRI) with implementation of diffusion-weighted imaging (DWI) where early ischemic lesions demonstrate increased water level in echo-planar imaging [3]. Pathophysiology definition of ischemic stroke occurs when the blood flow to an area of the brain is interrupted, resulting in some degree of permanent neurological damage [4]. The common pathway of ischemic stroke is lack of sufficient blood flow to perfuse cerebral tissue, due to narrowed or blocked arteries leading to or within the brain. Ischemic strokes can be subdivided into thrombotic and embolic strokes [5]. It is estimated that stroke is the second cause of death after cardiovascular disease and cancer in both low - and high-income countries [6]. Furthermore, ischemic strokes constitute approximately 80% of all strokes [7]. Ischemic strokes can be subdivided into thrombotic and embolic strokes [8]. It is emphasized that pharmacological actions aiming at limiting the area of damage should also include maintaining protective functions of neurons and endothelial cells of vessels composing neurovascular units [9]. Stroke management changed significantly what constitutes natural course of modern stroke units, better medical care, and more targeted motor and speech rehabilitation engaged in the early stage [10]. Increasingly fibrinolytic treatment with recombinant tissue plasminogen activator (rt-PA) and embolectomy are used [11, 12]. There is no commonly accepted therapy targeted on neuroplasticity [13]. During the last decades, researchers searched for indicators of ischemic stroke and neuroplasticity in order to determine effective diagnostics, prognostic assessment, and therapy [14, 15]. Interest of biomarkers has begun since introduction of thrombolytic treatment possible to administer up to 4.5 h from onset of symptoms and in individual cases up to 6 h after fulfilling inclusion and exclusion criteria towards standards of management in acute ischemic phase—according to the American Heart Association (AHA)/American Stroke Association (ASA) [16].

1.1. Neuroplasticity

The brain is a complex network of various subsets of cells that have the ability to be reprogrammed and also structurally rebuild [17]. The main point of neuroplasticity is capability of stimulation by a variety of stimuli for modulation of brain activity [18]. Brain compensates damages through reorganization and creation of new connections among undamaged neurons [19]. After ischemia of cells, oxygen deprivation in neurons cascades destruction in focus of infarction being formed lasts for many hours, usually leading to progression of damage [20].

1.2. Future Approach

Future research will be focused on markers of brain damage and could aid in understanding mechanisms disturbing plasticity. One of these may be inflammatory reaction initiated immediately after stroke leading to neuron damage but also possibly demonstrating neuroprotective activity [21]. The scientists from the University of California, Harvard University, and Federal Polytechnic in Zurich provided that after injury of the spinal cord exists the increased expression on genes leading to growth of damaged axons in mice and rats [22].

1.3. Focus of Ischemia: Pathology

Ischemic stroke occurs as a result of two primary pathological processes including oxygen loss and interruption in glucose supply to specific brain regions [23]. Inhibition of energy supplies leads to dysfunction of neurotransmission [24]. It was observed that disturbance of neuron functions occurs when cerebral flow decreases to 50 ml/100 g/min [25]. Irreversible damage occurs when cerebral blood flow decreases consecutively to 30 ml/100 g/min [26]. The level and duration of decreased flow are associated with increasing probability of irreversible neuron damage [27]. In an event of blood flow arrest in cerebral tissue, neuronal metabolism is disturbed after 30 seconds, whereas in consecutive minutes of oxygen deficiency, cascade reaction begins, eventually leading to brain infarction [28, 29]. Among occurring reactions included are as follows: local dilation of vessels, circulatory disturbances in vessels, local swelling, and necrosis [30]. Alternations on the neuronal level lead to disturbed functional activity of cells and their apoptosis [31]. These disturbances originate from dysfunction of Na+/K+ATPase leading to depolarization of neuronal membrane, releasing excitatory neurotransmitters and opening of calcium (Ca2+) channels [32]. Secondary damage of neurons and cell organelles and further dysregulation of cellular metabolism occur [33]. In this case, Ca2+ ions spread intracellularly through channels gated with potential or receptors that may be additionally induced by several neurotransmitters in excitotoxicity mechanism [34, 35]. More delayed processes accompanying stroke are related to the neuroinflammatory process and cellular apoptosis initiated within a number of minutes after ischemic attack and may last for even several weeks and months [36]. These events may lead to delayed death of neurons and are subject of vast research concerning neuroprotective theories and agents [37]. Complex background of events following an ischemic episode hinders successful design of effective therapeutic strategies. Current research is directed at neuroprotective and proregenerative therapies which may aid recovery of lost functions by neurons after an ischemic episode. Studies have proven that regeneration after stroke and recovery of lost functions may be assigned to neuronal plasticity understood as the ability of the brain to reorganize and rebuild as an effect of changed environmental conditions [38]. It is well known that ischemic stroke triggers inflammatory cascade through activation of numerous cell mediators. Ischemia leads to accumulation of glutamate (Glu) in extracellular space and excitotoxicity [39]. In ischemic tissue, reactive oxygen species are generated and blood-brain barrier (BBB) integration is significantly disturbed [40]. Microglia are the first line of cells reacting on damage and primary source of proinflammatory cytokines and chemokines [41, 42]. Their release causes local activation of microglia, intensification of cell adhesion, and mobilization of leukocytes [43]. Increased oxidative stress and cytokine activation contribute to further intensification of inflammatory process including regulation of matrix metalloproteinase (MMP) from astrocytes and microglia leading to BBB dysfunction and eventually death of neurons [44]. Ageing decreases capabilities of neurons for functional plasticity in a healthy brain [45]. Regaining lost functions may be explained by neuronal plasticity and decreased ability for reorganization possibly being a significant factor causing a worse functional result in elderly patients [46]. For better understanding of neuroplasticity, tracking of genetic changes influencing it is needed [47]. As many neuronal processes influencing neuroplasticity depend on expression of particular genes and genetic diversity possibly influencing its effectiveness, knowledge on their mechanisms is necessary to understand this process. Epigenetic mechanisms occurring after stroke will be briefly discussed in this paper. Background of epigenetic changes is characterized by several mechanisms such as synaptic plasticity; neuro-, glio-, and angiogenesis processes; and growth of axon. Each of these processes is modified molecularly through DNA methylation, histone modification, and microRNA (miRNA) actions.

2. Neuronal Plasticity

Synaptic plasticity is achieved through improvement of communication in synaptic connections between existing neurons and is fundamental for retaining neuronal networks [48]. Its very important information surrounding the focus of ischemia is the existing area name penumbra. Immediately following the event, blood flow and therefore oxygen transport are reduced locally, leading to hypoxia of the cells near the location of the original insult. This can lead to hypoxic cell death (infarction) and amplify the original damage from the ischemia; however, the penumbra area may remain viable for several hours after an ischemic event due to the collateral arteries that supply the penumbral zone. As time elapses after the onset of stroke, the extent of the penumbra tends to decrease; therefore, in the emergency department, a major concern is to protect the penumbra by increasing oxygen transport and delivery to cells in the danger zone, thereby limiting cell death. The existence of a penumbra implies that salvage of the cells is possible. There is a high correlation between the extent of spontaneous neurological recovery and the volume of penumbra that escapes infarction; therefore, saving the penumbra should improve the clinical outcome [49]. Epigenetic regulation, which involves DNA methylation and histone modifications, plays a critical role in retaining long-term changes in postmitotic cells. Accumulating evidence suggests that the epigenetic machinery might regulate the formation and stabilization of long-term memory in two ways: a “gating” role of the chromatin state to regulate activity-triggered gene expression and a “stabilizing” role of the chromatin state to maintain molecular and cellular changes induced by the memory-related event. The neuronal activation regulates the dynamics of the chromatin status under precise timing, with subsequent alterations in the gene expression profile.

2.1. DNA Methylation

In the study of Levenson and Sweatt in 2005, they proved that DNA methyltransferase enzyme family (DNMT) is important for synaptic plasticity [50]. Inhibition of DNMT activity causes long-term blockade of hippocampus potentiation and leads to decreased methylation of protein promoters called reelin, brain-derived neurotrophic factor (BDNF), and other genes participating in synaptic plasticity. Increased excitability within the penumbra is associated with dynamic regulation of DNA methylation [51, 52]. One of the most interesting phenomena is the process of active demethylation of gene promoter regions of BDNF through growth arrest and DNA-damage-inducible beta (GADD45B) protein activity. The role of GADD45B as a key DNA demethylation coordinator is mostly based only on in vivo experiments; however, it is difficult to distinguish active from passive demethylation of DNA. N-Methyl-D-aspartate (NMDA) agonism is found to induce expression of GADD45B mRNA and BDNF, at the same time reducing mRNA expression [53]. Ma et al. in 2009 documented that BDNF IXa is demethylated by GADD45b in mice [54]. Although there are regulatory differences between human BDNF IXabcd and mouse BDNF IXa [55], there also exist several similarities. In vivo and in vitro human BDNF IXabcd and mouse BDNF IXa are similarly induced by neuronal activity [56].

2.2. Histone Modifications

Histone modifications protruding from the nucleosome core are acetylated or deacetylated. It is an epigenetic mechanism for controlling gene expression. A very important epigenetic mechanism for controlling gene expression is posttranslational modification of histones. In that modification, the rest of lysine at the N-terminus are acetylated or deacetylated. The function of histone lysine deacetylase (HDAC2) is not limited to long-term synaptic potentiation; it also includes creation of memory in the hippocampus [57]. In anatomical terms, inhibition of HDAC2 significantly increases creation of dendritic bridges in neurons of the hippocampus. It is now evident that integration and regulation of epigenetic modifications allow for complex control of gene expression necessary for long-term memory formation and maintenance. Dynamic changes in DNA methylation and chromatin structure are the result of well-established intracellular signaling cascades that converge on the nucleus to adjust the precise equilibrium of gene repression and activation [58].

2.3. miRNA

miRNAs are endogenous, noncoding RNAs that take part in the posttranscriptional regulation of gene expression mainly by binding to the 3-untranslated region of messenger RNAs (mRNAs). A few of miRNAs which are isolated from brain play an important role in synaptic plasticity. They also take important part in learning and memory function [59].

Activity-regulated cytoskeleton-associated protein (ARC) gene is an important regulator of synaptic plasticity. Its expression is decreased in the ischemic cortex and significantly increased in the tissue cortex surrounding ischemic focus shortly after stroke, probably as an effect of Glu release and activation of neurons [60]. ARC expression is regulated by multiple miRNAs and ectopic miRNA expression in hippocampal neurons and by inhibition of the endogenous miRNAs in neurons. Frisén in 2016 proved that during in vitro neuronal development, there is an inverse relationship between ARC mRNA expression and expression of ARC-targeting miRNAs. Thus, at DIV10, expressions of miR-19a, miR-34a, miR-326, and miR-193a were decreased while ARC mRNA was elevated [61].

3. Neuro-, Glio-, and Angiogenesis

Taking into consideration that synaptic plasticity is achieved through improvement of communication in synapses between existing neurons, the terms neuro-, glio-, and angiogenesis refer to development and formation of new neurons and blood vessels in the brain [6264]. Recently, it has been proved that formation of new neurons is not limited to the time before birth [65, 66]. However, in order for neurogenesis to occur, one condition must be fulfilled, that is, presence of stem cells and progenitor cell and special types of cells in the dentate gyrus, in the hippocampus, and possibly in the prefrontal cortex which will become completely equipped neuron with axons and dendrites [67, 68]. New neurons can migrate to distant areas of the brain to fulfill important and previously lost functions [69]. Neuronal death is a strong stimulant for neurogenesis after ischemic stroke [70, 71]. Ischemic event is followed by increased formation of cells from these regions and alteration of migration pathways toward damaged area [7274]. The majority of cells die and very few participate in this process [75]. Recently, researchers use the denomination of “neurovascular unit.” The neurovascular unit involves connection of neurons with blood vessels and involves growth factors influencing neurogenesis which indirectly affect angiogenesis [76]. Neurogenesis and angiogenesis occur after ischemic stroke. It is modulated by DNA methylation, histone modification, and miRNA actions. The formation of long-term memory involves a series of molecular and cellular changes, including gene transcription, protein synthesis, and synaptic plasticity dynamics [77].

3.1. DNA Methylation

Methylation silences gene expression in a variety of ways, one of which is recruitment of specific binding proteins to an element of promoter [78]. The family of methyl-CpG-binding domain (MBD) binding proteins include MBD1-4 and methyl-CpG-binding protein 2 (MECP2). The scientists observed increase of MBD1 and MECP2 after 24 hours of stroke, and expression of MBD2 increases after 6 h from ischemia [79]. All mentioned proteins have regulatory functions in neurogenesis process [80]. DNA methylation was recognized in the past as a highly stable gene silencing method. At present, evidence suggests that methylation states may be more dynamic than it was previously assumed [81]. Growth arrest and DNA damage 45 (GADD45) proteins are significant elements of active cytosine (Cys) residue demethylation process [82]. The process is mediated by DNA repair pathway. GADD45 may function through feedback of necessary enzymatic process in which demethylation could lead to increased expression of specific genes significant for neuroplasticity.

3.2. Histone Modifications

Particular elements of polycomb-group proteins participate in neurogenesis [83]. Formation of oligodendrocytes is also transformed during stroke with histone deacetylase. It is already in the acute phase of stroke that oligodendrocyte progenitor cells (OPC) in the white matter of penumbra demonstrate increased protein expression of HDAC1 and HDAC2 along with increased proliferation [84]. What is more particular, HDAC isoforms may have diverse impact on cell maturation [85]. In their study, Wang et al. in 2012 demonstrated that valproic acid (VPA), a strong histone deacetylase inhibitor, has impact on regaining functions after stroke. That acid additionally increases the density of blood vessels thus improving cerebral blood flow to the ischemic hemisphere 14 days after stroke [86]. It was also demonstrated that VPA mediates in regeneration through promoting neuronal diversity in hippocampus progenitor cells [87].

3.3. miRNA

The role of miRNA was widely recognized as a regulator in neurogenesis. As previously stated, miR-124 is important in the acute phase of stroke. This is a ligand Jagged1 (JAG1) targeting as a neuronal determinant in the normal subventricular zone (SVZ) [88]. That miRNA influences repair after stroke through regulation of behavior of progenitor cells. In the brain with ischemia, miR-124 is reduced in the SVZ for 7 days after stroke that corresponds with time of significant neurogenesis [89]. Another miRNA transcript potentially important for brain repair after stroke is miR-9 [90]. Its loss inhibits proliferation in human neuronal progenitor cells and intensifies migration of these cells after transplantation to the ischemic brain [91].

4. Axon Growth

The growth of the axon becomes the main requirement for plasticity and recovery of lost functions. The axon regrowth depends on several neurobiological modifications such as the level of myelination and synapse formation. Despite the ability of axons to grow by altering the extracellular and intracellular substances, dedifferentiation in which axons are responsible for recovering functions from those that are functionally silent is still a matter of discussion. In this case, the intuitive translation relation between anatomical and functional regeneration is questioned [92]. In ischemic stroke as well as in brain injury, the area of brain damage is characterized by the formation of glial scar, in which growth inhibitors are upregulated; preventing the effective regeneration of this scar is characterized by significant upregulation of proteoglycans, preventing the effective regeneration of axons. In the close proximity to the glial scar, however, there is a cortical area that is characterized by the expression of many growth-promoting factors that allow axonal growth [93]. One of the main components of glial scars is extracellular matrix proteins known as CSPG, which consist of protein chains and glycosaminoglycans (GAGs). CSPGs are present in the developing and also adult central nervous system, but their expression significantly increases after injury. Reactive astrocytes are responsible for the production and secretion of many CSPGs after injury, and their increased expression is observed for many months. Two reasons for the failure of the CNS regeneration are extrinsic inhibitory molecules and poor internal growth ability [94].

4.1. DNA Methylation

Descriptions of the mechanism of DNA methylation in axon growth regulation after stroke are based on published postinjury models; we do not have any models of ischemia [95]. Therefore, recreation of ischemic conditions is difficult. An important role in promoting axon number growth has been recently attributed to proline-rich protein (SPRR1) released after axotomy [96]. High concentration of SPRR1 is released in the cortex of ischemic focus in the initial phase of stroke.

4.2. Histone Modifications

SPRR1 may be induced by hypomethylating agents and its expression may be modulated by histone modification [97]. Similarly to the impact of 5-azacytidine on keratinocytes, SPRR1 expression is increased in these cells after treatment with an HDAC inhibitor such as sodium butyrate. Nowadays, we do not have examinations on the human brain [98]. Growth-Associated Protein 43 (GAP43) consists of protein related with a growth cone promoting growth of axons through regulation of cytoskeleton organization with protein kinase C signaling. That expression is strongly induced in the ischemic cortex after ischemic stroke [99]. According to Yuan et al. in 2001, administration of VPA may induce expression of GAP43 as well as of other growth proteins simultaneously promoting regeneration of axons [100].

4.3. miRNA

The most important role in the growth of axon is played by miRNA [101, 102]. The role of miR-9, whose level is reduced in the ischemic white matter, is best known. Therefore, miR-9 is released in primary axons of the neuron cortex of a developing brain. miR-9 replicates microtubule-associated protein 1B (MAP1B) connected with a cytoskeleton [103]. That inhibition occurs through RNA interference resulting not only in a significantly increased length of axon but also in a decreased pattern of branches. As in the case of two previous processes, the issue of growth of axon requires further research.

5. Discussion

Neuroplasticity is a widespread phenomenon in the function of the nervous system. Spontaneous recovery is the norm in the early poststroke period. Cortical reorganization is common and necessary for postbrain injury recovery. Representations of sensory and motor cortical areas may be modified by the inflow of environmental stimulation during learning and memory processes. Physiotherapy strategies used during recovery process affect the spontaneous neuroplasticity. After stroke, the main functional dysfunctions are aphasia and hemiplegia. Regarding the dynamic changes of a clinical picture of a patient after an ischemic episode, multiplicity, and diversity of pathology, the doctors, physiotherapists, and speech therapists do not have a universal procedure or concept.

A correct therapy depends on the actual deficit and patient necessity [104, 105]. Neural plasticity allows progress of the central nervous system under the influence of variable conditioning environment, learning, and memorization; the new abilities and adaptation into changes happen inside and outside of entourage and activity compensatory process after ischemia. It happens because of a neuron’s property enabling overlap indicating changes in the neuronal system in response to organism’s needs and challenge of reality [106]. Daily activity, learning, and training have a main influence on brain function. Developing right connections through axons, projections, synapse, and chemical transmitter is an ongoing intricate process with different intensities all throughout the human life. His course determines the information written in the DNA. Genetic predisposition is modified as a result of experience; throughout human life, through environmental changes, the number of synaptic pathways can rise. Many new emerging neuronal cells succumb apoptosis—programmed and irreversible autodestruction—and pruning. The elements of neurons, for example, mitochondria in apoptotic bodies, are removed by macrophages or absorbed through familiar cells. Overproduction of neurons is necessary to obtain an appropriate number of synaptic pathways that kill these cells who cannot create connection functional active [107].

A properly carried out treatment achieves skills by allowing rehabilitation to move beyond the walls of the hospital or home, and this contributes to the functional independence of patients.

Researchers and therapists are still looking for a new possibility of impact of the neuronal system; it will contribute in the future to the functional progress and usage capacity of the mechanisms of neuronal plasticity in the case of his damage [108].

In many sciences, it was confirmed a fact that in regular methodical learning, we can considerably increase intellectual capacity and correct memory, concentration, and logical thinking, and in the case of neurological disorder by targeting the process of neural compensatory plasticity, we can obtain significant improvement of disturbed performance. The effects of neural plasticity depends on the clinical factor, age, intellect, and education of patient. In well-educated people, there exists cognitive reserve of the brain, which may have an impact on the recovery process [109].

A small group of scientists studied Albert Einstein’s brain in search of special abilities in the structure of the neuronal system. They compared with another four brains from other people who died at the same age. They discovered in the brain of Albert Einstein a difference in the cytoarchitecture when compared with brains of other people. They found out a higher ratio of astrocytes to neurons in the cerebral cortex parietal lobe in the left hemispheres. Glial cells enable provision of nutritional substances to the brain through connection with the blood vessel, from which we conclude that astroglia can be a ground for neural plasticity [110]. Among many methods of streamlining patients with hemiplegia, we use proprioceptive neuromuscular facilitation (PNF), neurodevelopmental treatment (NDT)/Bobath, constraint-induced movement therapy (CIMT), training oriented on top of approach task-oriented training, neuromuscular arthroskeletal plasticity (NAP), and occupational therapy based on the aim with the rule SMART—specified, measured, attractive, real, and timely. We must select every time a therapy which adapts into individual needs and ability of patient [111]. Neural plasticity allows progress of the central nervous system under the influence of variable conditioning environment, learning, and memorization and the new abilities and adaptation into changes happen inside and outside of entourage and activity compensatory process after ischemia. It happens because of the neuron’s property enabling overlap indicating changes in the neuronal system in response to the organism’s needs and challenge of reality [112, 113].

According to the above considerations and analyses, it should be indicated that an issue of ischemic stroke not only constitutes individual physical and social impairments but also represents significant financial burden for the global health care systems concerning professionally active people in productive age [114116]. Patients after an ischemic episode frequently become dependent on institutional organization [117]. Return to daily living and professional activity is hindered, often impossible, for these patients, leading to dependence on the closest relatives [118, 119]. Necessity to help a disabled person causes dysregulation of social and professional life of careers [120]. Optimally, clinical experience should be combined with search for new forms of brain functional reserve [121]. Recovery after stroke is a complex phenomenon. In a study of anti-inflammatory strategies that have been effective for recovery in experimental stroke, Liguz-Lecznar and Kossut described that the most important aspect of therapies targeting the immune system will be regulating the balance between the neurotoxic and neuroprotective effects of inflammatory state components [122]. Clinical experience, awareness of the scale of the problem, and molecular research may be used in combination with each other. It may be assumed that combination of new therapies with neurologic rehabilitation could be a new trend in the treatment of patients after stroke. Another stroke-related issue concerns the substantial prevention. The stroke prevention should consist of complex medical and political issues [123]. We strongly believe that issues discussed in this study should allow better understanding of physiological background and other social aspects of escalating problem of stroke indicating future research directions.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

References

  1. S. Hatano, “Experience from a multicentre stroke register: a preliminary report,” Bulletin of the World Health Organization, vol. 54, no. 5, pp. 541–553, 1976. View at Google Scholar
  2. A. G. Sorensen and H. Ay, “Transient ischemic attack: definition, diagnosis, and risk stratification,” Neuroimaging Clinics of North America, vol. 21, no. 2, pp. 303–313, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. J. Liang, P. Gao, Y. Lin, L. Song, H. Qin, and B. Sui, “Susceptibility-weighted imaging in post-treatment evaluation in the early stage in patients with acute ischemic stroke,” Journal of International Medical Research, vol. 47, no. 1, pp. 196–205, 2018. View at Publisher · View at Google Scholar
  4. R. L. Sacco, S. E. Kasner, J. P. Broderick et al., “An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association,” Stroke, vol. 44, no. 7, pp. 2064–2089, 2013. View at Publisher · View at Google Scholar · View at Scopus
  5. T. D. Musuka, S. B. Wilton, M. Traboulsi, and M. D. Hill, “Diagnosis and management of acute ischemic stroke: speed is critical,” Canadian Medical Association Journal, vol. 187, no. 12, pp. 887–893, 2015. View at Publisher · View at Google Scholar · View at Scopus
  6. D. Della-Morte, F. Guadagni, R. Palmirotta et al., “Genetics of ischemic stroke, stroke-related risk factors, stroke precursors and treatments,” Pharmacogenomics, vol. 13, no. 5, pp. 595–613, 2012. View at Publisher · View at Google Scholar · View at Scopus
  7. L. Brewer, F. Horgan, A. Hickey, and D. Williams, “Stroke rehabilitation: recent advances and future therapies,” QJM, vol. 106, no. 1, pp. 11–25, 2012. View at Publisher · View at Google Scholar · View at Scopus
  8. M. Chouchane and M. R. Costa, “Cell therapy for stroke: use of local astrocytes,” Frontiers in Cellular Neuroscience, vol. 6, 2012. View at Publisher · View at Google Scholar
  9. R. Khatib, A. M. Jawaada, Y. A. Arevalo, H. K. Hamed, S. H. Mohammed, and M. D. Huffman, “Implementing evidence-based practices for acute stroke care in low- and middle-income countries,” Current Atherosclerosis Reports, vol. 19, no. 12, p. 61, 2017. View at Publisher · View at Google Scholar · View at Scopus
  10. K. Gache, H. Leleu, G. Nitenberg, F. Woimant, M. Ferrua, and E. Minvielle, “Main barriers to effective implementation of stroke care pathways in France: a qualitative study,” BMC Health Services Research, vol. 14, no. 1, 2014. View at Publisher · View at Google Scholar · View at Scopus
  11. T. R. Lawson, I. E. Brown, D. L. Westerkam et al., “Tissue plasminogen activator (rt-PA) in acute ischemic stroke: outcomes associated with ambulation,” Restorative Neurology and Neuroscience, vol. 33, no. 3, pp. 301–308, 2015. View at Publisher · View at Google Scholar · View at Scopus
  12. A. J. Yoo and T. Andersson, “Thrombectomy in acute ischemic stroke: challenges to procedural success,” Journal of Stroke, vol. 19, no. 2, pp. 121–130, 2017. View at Publisher · View at Google Scholar · View at Scopus
  13. H. Kaur, A. Prakash, and B. Medhi, “Drug therapy in stroke: from preclinical to clinical studies,” Pharmacology, vol. 92, no. 5-6, pp. 324–334, 2013. View at Publisher · View at Google Scholar · View at Scopus
  14. G. C. Jickling and F. R. Sharp, “Blood biomarkers of ischemic stroke,” Neurotherapeutics, vol. 8, no. 3, pp. 349–360, 2011. View at Publisher · View at Google Scholar · View at Scopus
  15. E. Burke and S. C. Cramer, “Biomarkers and predictors of restorative therapy effects after stroke,” Current Neurology and Neuroscience Reports, vol. 13, no. 2, p. 329, 2013. View at Publisher · View at Google Scholar · View at Scopus
  16. W. J. Powers, A. A. Rabinstein, T. Ackerson et al., “2018 guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association,” Stroke, vol. 49, no. 3, pp. e46–e110, 2018. View at Publisher · View at Google Scholar · View at Scopus
  17. M. Götz and S. Jarriault, “Programming and reprogramming the brain: a meeting of minds in neural fate,” Development, vol. 144, no. 15, pp. 2714–2718, 2017. View at Publisher · View at Google Scholar · View at Scopus
  18. P. Voss, M. E. Thomas, J. M. Cisneros-Franco, and E. de Villers-Sidani, “Dynamic brains and the changing rules of neuroplasticity: implications for learning and recovery,” Frontiers in Psychology, vol. 8, 2017. View at Publisher · View at Google Scholar · View at Scopus
  19. M. P. Lin and D. S. Liebeskind, “Imaging of ischemic stroke,” Continuum: Lifelong Learning in Neurology, vol. 22, no. 5, pp. 1399–1423, 2016. View at Publisher · View at Google Scholar · View at Scopus
  20. M. Sumer, I. Ozdemir, and O. Erturk, “Progression in acute ischemic stroke: frequency, risk factors and prognosis,” Journal of Clinical Neuroscience, vol. 10, no. 2, pp. 177–180, 2003. View at Publisher · View at Google Scholar · View at Scopus
  21. S. C. Cramer, M. Sur, B. H. Dobkin et al., “Harnessing neuroplasticity for clinical applications,” Brain, vol. 134, no. 6, pp. 1591–1609, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Anrather and C. Iadecola, “Inflammation and stroke: an overview,” Neurotherapeutics, vol. 13, no. 4, pp. 661–670, 2016. View at Publisher · View at Google Scholar · View at Scopus
  23. N. M. Robbins and R. A. Swanson, “Opposing effects of glucose on stroke and reperfusion injury: acidosis, oxidative stress, and energy metabolism,” Stroke, vol. 45, no. 6, pp. 1881–1886, 2014. View at Publisher · View at Google Scholar · View at Scopus
  24. C. Xing, K. Arai, E. H. Lo, and M. Hommel, “Pathophysiologic cascades in ischemic stroke,” International Journal of Stroke, vol. 7, no. 5, pp. 378–385, 2012. View at Publisher · View at Google Scholar · View at Scopus
  25. H. Jaffer, V. B. Morris, D. Stewart, and V. Labhasetwar, “Advances in stroke therapy,” Drug Delivery and Translational Research, vol. 1, no. 6, pp. 409–419, 2011. View at Publisher · View at Google Scholar · View at Scopus
  26. N. Mitsios, J. Gaffney, P. Kumar, J. Krupinski, S. Kumar, and M. Slevin, “Pathophysiology of acute ischaemic stroke: an analysis of common signalling mechanisms and identification of new molecular targets,” Pathobiology, vol. 73, no. 4, pp. 159–175, 2006. View at Publisher · View at Google Scholar · View at Scopus
  27. O. Y. Bang, J. L. Saver, J. R. Alger et al., “Determinants of the distribution and severity of hypoperfusion in patients with ischemic stroke,” Neurology, vol. 71, no. 22, pp. 1804–1811, 2008. View at Publisher · View at Google Scholar · View at Scopus
  28. C. Xiao and R. M. Robertson, “Timing of locomotor recovery from anoxia modulated by the white gene in Drosophila,” Genetics, vol. 203, no. 2, pp. 787–797, 2016. View at Publisher · View at Google Scholar · View at Scopus
  29. I. M. Macrae and S. M. Allan, “Stroke: the past, present and future,” Brain and Neuroscience Advances, vol. 2, article 2398212818810689, 2018. View at Publisher · View at Google Scholar
  30. J. A. Stokum, V. Gerzanich, and J. M. Simard, “Molecular pathophysiology of cerebral edema,” Journal of Cerebral Blood Flow and Metabolism, vol. 36, no. 3, pp. 513–538, 2016. View at Publisher · View at Google Scholar · View at Scopus
  31. D. Radak, N. Katsiki, I. Resanovic et al., “Apoptosis and acute brain ischemia in ischemic stroke,” Current Vascular Pharmacology, vol. 15, no. 2, pp. 115–122, 2017. View at Publisher · View at Google Scholar · View at Scopus
  32. M. J. Kim, J. Hur, I. H. Ham et al., “Expression and activity of the na-k ATPase in ischemic injury of primary cultured astrocytes,” The Korean Journal of Physiology & Pharmacology, vol. 17, no. 4, pp. 275–281, 2013. View at Publisher · View at Google Scholar · View at Scopus
  33. L. Watts, R. Lloyd, R. Garling, and T. Duong, “Stroke neuroprotection: targeting mitochondria,” Brain Sciences, vol. 3, no. 4, pp. 540–560, 2013. View at Publisher · View at Google Scholar · View at Scopus
  34. S. Ding, “Ca2+ signaling in astrocytes and its role in ischemic stroke,” Advances in Neurobiology, vol. 11, pp. 189–211, 2014. View at Publisher · View at Google Scholar
  35. T. W. Lai, S. Zhang, and Y. T. Wang, “Excitotoxicity and stroke: identifying novel targets for neuroprotection,” Progress in Neurobiology, vol. 115, pp. 157–188, 2014. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Vidale, A. Consoli, M. Arnaboldi, and D. Consoli, “Postischemic inflammation in acute stroke,” Journal of Clinical Neurology, vol. 13, no. 1, pp. 1–9, 2017. View at Publisher · View at Google Scholar · View at Scopus
  37. A. Majid, “Neuroprotection in stroke: past, present, and future,” ISRN Neurology, vol. 2014, Article ID 515716, 17 pages, 2014. View at Publisher · View at Google Scholar
  38. C. Alia, C. Spalletti, S. Lai et al., “Neuroplastic changes following brain ischemia and their contribution to stroke recovery: novel approaches in neurorehabilitation,” Frontiers in Cellular Neuroscience, vol. 11, 2017. View at Publisher · View at Google Scholar · View at Scopus
  39. A. Brassai, R. G. Suvanjeiev, E. G. Bán, and M. Lakatos, “Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity,” Brain Research Bulletin, vol. 112, pp. 1–6, 2015. View at Publisher · View at Google Scholar · View at Scopus
  40. A. E. Sifat, B. Vaidya, and T. J. Abbruscato, “Blood-brain barrier protection as a therapeutic strategy for acute ischemic stroke,” The AAPS Journal, vol. 19, no. 4, pp. 957–972, 2017. View at Publisher · View at Google Scholar · View at Scopus
  41. Y. B. Lee, A. Nagai, and S. U. Kim, “Cytokines, chemokines, and cytokine receptors in human microglia,” Journal of Neuroscience Research, vol. 69, no. 1, pp. 94–103, 2002. View at Publisher · View at Google Scholar · View at Scopus
  42. R. Guruswamy and A. ElAli, “Complex roles of microglial cells in ischemic stroke pathobiology: new insights and future directions,” International Journal of Molecular Sciences, vol. 18, no. 3, 2017. View at Publisher · View at Google Scholar · View at Scopus
  43. A. R. Patel, R. Ritzel, L. D. McCullough, and F. Liu, “Microglia and ischemic stroke: a double-edged sword,” International Journal of Physiology, Pathophysiology and Pharmacology, vol. 5, no. 3, pp. 73–90, 2013. View at Google Scholar
  44. S. E. Lakhan, A. Kirchgessner, D. Tepper, and A. Leonard, “Matrix metalloproteinases and blood-brain barrier disruption in acute ischemic stroke,” Frontiers in Neurology, vol. 4, 2013. View at Publisher · View at Google Scholar · View at Scopus
  45. S. N. Burke and C. A. Barnes, “Neural plasticity in the ageing brain,” Nature Reviews Neuroscience, vol. 7, no. 1, pp. 30–40, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. M. J. Spriggs, C. J. Cadwallader, J. P. Hamm, L. J. Tippett, and I. J. Kirk, “Age-related alterations in human neocortical plasticity,” Brain Research Bulletin, vol. 130, pp. 53–59, 2017. View at Publisher · View at Google Scholar · View at Scopus
  47. K. M. Pearson-Fuhrhop and S. C. Cramer, “Genetic influences on neural plasticity,” PM&R, vol. 2, 12 Supplement 2, pp. S227–S240, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. J. D. Power and B. L. Schlaggar, “Neural plasticity across the lifespan,” Wiley Interdisciplinary Reviews: Developmental Biology, vol. 6, no. 1, p. e216, 2017. View at Publisher · View at Google Scholar · View at Scopus
  49. J. V. Guadagno, C. Calautti, and J.-C. Baron, “Progress in imaging stroke: emerging clinical applications,” British Medical Bulletin, vol. 65, no. 1, pp. 145–157, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. J. M. Levenson and J. D. Sweatt, “Epigenetic mechanisms in memory formation,” Nature Reviews Neuroscience, vol. 6, no. 2, pp. 108–118, 2005. View at Publisher · View at Google Scholar · View at Scopus
  51. K. Schiene, C. Bruehl, K. Zilles et al., “Neuronal hyperexcitability and reduction of GABAA-receptor expression in the surround of cerebral photothrombosis,” Journal of Cerebral Blood Flow and Metabolism, vol. 16, no. 5, pp. 906–914, 1996. View at Publisher · View at Google Scholar · View at Scopus
  52. J. U. Guo, Y. Su, C. Zhong, G. L. Ming, and H. Song, “Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond,” Cell Cycle, vol. 10, no. 16, pp. 2662–2668, 2011. View at Publisher · View at Google Scholar · View at Scopus
  53. D. K. Ma, J. U. Guo, G. L. Ming, and H. Song, “DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation,” Cell Cycle, vol. 8, no. 10, pp. 1526–1531, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. D. K. Ma, M. H. Jang, J. U. Guo et al., “Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis,” Science, vol. 323, no. 5917, pp. 1074–1077, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. P. Pruunsild, A. Kazantseva, T. Aid, K. Palm, and T. Timmusk, “Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters,” Genomics, vol. 90, no. 3, pp. 397–406, 2007. View at Publisher · View at Google Scholar · View at Scopus
  56. P. Pruunsild, M. Sepp, E. Orav, I. Koppel, and T. Timmusk, “Identification of cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene,” Journal of Neuroscience, vol. 31, no. 9, pp. 3295–3308, 2011. View at Publisher · View at Google Scholar · View at Scopus
  57. S. Chatterjee, P. Mizar, R. Cassel et al., “A novel activator of CBP/p300 acetyltransferases promotes neurogenesis and extends memory duration in adult mice,” Journal of Neuroscience, vol. 33, no. 26, pp. 10698–10712, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. J. S. Guan, S. J. Haggarty, E. Giacometti et al., “HDAC2 negatively regulates memory formation and synaptic plasticity,” Nature, vol. 459, no. 7243, pp. 55–60, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. W. Liu, J. Wu, J. Huang et al., “Electroacupuncture regulates hippocampal synaptic plasticity via miR-134-mediated LIMK1 function in rats with ischemic stroke,” Neural Plasticity, vol. 2017, Article ID 9545646, 11 pages, 2017. View at Publisher · View at Google Scholar · View at Scopus
  60. J. D. Shepherd and M. F. Bear, “New views of Arc, a master regulator of synaptic plasticity,” Nature Neuroscience, vol. 14, no. 3, pp. 279–284, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. J. Frisén, “Neurogenesis and gliogenesis in nervous system plasticity and repair,” Annual Review of Cell and Developmental Biology, vol. 32, no. 1, pp. 127–141, 2016. View at Publisher · View at Google Scholar · View at Scopus
  62. G. L. Ming and H. Song, “Adult neurogenesis in the mammalian brain: significant answers and significant questions,” Neuron, vol. 70, no. 4, pp. 687–702, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. T. D. Palmer, J. Ray, and F. H. Gage, “FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain,” Molecular and Cellular Neurosciences, vol. 6, no. 5, pp. 474–486, 1995. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Rosi, “Neuroinflammation and the plasticity-related immediate-early gene Arc,” Brain, Behavior, and Immunity, vol. 25, Supplement 1, pp. S39–S49, 2011. View at Publisher · View at Google Scholar · View at Scopus
  65. N. Kaneko, M. Sawada, and K. Sawamoto, “Mechanisms of neuronal migration in the adult brain,” Journal of Neurochemistry, vol. 141, no. 6, pp. 835–847, 2017. View at Publisher · View at Google Scholar · View at Scopus
  66. A. Pino, G. Fumagalli, F. Bifari, and I. Decimo, “New neurons in adult brain: distribution, molecular mechanisms and therapies,” Biochemical Pharmacology, vol. 141, pp. 4–22, 2017. View at Publisher · View at Google Scholar · View at Scopus
  67. C. Göritz and J. Frisén, “Neural stem cells and neurogenesis in the adult,” Cell Stem Cell, vol. 10, no. 6, pp. 657–659, 2012. View at Publisher · View at Google Scholar · View at Scopus
  68. P. S. Eriksson, E. Perfilieva, T. Björk-Eriksson et al., “Neurogenesis in the adult human hippocampus,” Nature Medicine, vol. 4, no. 11, pp. 1313–1317, 1998. View at Publisher · View at Google Scholar · View at Scopus
  69. Y.-F. Liu, H.-I. Chen, C.-L. Wu et al., “Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I,” The Journal of Physiology, vol. 587, no. 13, pp. 3221–3231, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. K. V. Adams and C. M. Morshead, “Neural stem cell heterogeneity in the mammalian forebrain,” Progress in Neurobiology, vol. 170, pp. 2–36, 2018. View at Publisher · View at Google Scholar · View at Scopus
  71. O. Lindvall and Z. Kokaia, “Neurogenesis following stroke affecting the adult brain,” Cold Spring Harbor Perspectives in Biology, vol. 7, no. 11, article a019034, 2015. View at Publisher · View at Google Scholar · View at Scopus
  72. R. J. Felling, M. J. Snyder, M. J. Romanko et al., “Neural stem/progenitor cells participate in the regenerative response to perinatal hypoxia/ischemia,” Journal of Neuroscience, vol. 26, no. 16, pp. 4359–4369, 2006. View at Publisher · View at Google Scholar · View at Scopus
  73. A. Arvidsson, T. Collin, D. Kirik, Z. Kokaia, and O. Lindvall, “Neuronal replacement from endogenous precursors in the adult brain after stroke,” Nature Medicine, vol. 8, no. 9, pp. 963–970, 2002. View at Publisher · View at Google Scholar · View at Scopus
  74. P. Thored, A. Arvidsson, E. Cacci et al., “Persistent production of neurons from adult brain stem cells during recovery after stroke,” Stem Cells, vol. 24, no. 3, pp. 739–747, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. S. W. Hou, Y. Q. Wang, M. Xu et al., “Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain,” Stroke, vol. 39, no. 10, pp. 2837–2844, 2008. View at Publisher · View at Google Scholar · View at Scopus
  76. C. Xing, K. Hayakawa, J. Lok, K. Arai, and E. H. Lo, “Injury and repair in the neurovascular unit,” Neurological Research, vol. 34, no. 4, pp. 325–330, 2012. View at Publisher · View at Google Scholar · View at Scopus
  77. J. J. Ohab, S. Fleming, A. Blesch, and S. T. Carmichael, “A neurovascular niche for neurogenesis after stroke,” Journal of Neuroscience, vol. 26, no. 50, pp. 13007–13016, 2006. View at Publisher · View at Google Scholar · View at Scopus
  78. J. S. Guan, H. Xie, and X. Ding, “The role of epigenetic regulation in learning and memory,” Experimental Neurology, vol. 268, pp. 30–36, 2015. View at Publisher · View at Google Scholar · View at Scopus
  79. B. P. Jung, G. Zhang, W. Ho, J. Francis, and J. H. Eubanks, “Transient forebrain ischemia alters the mRNA expression of methyl DNA-binding factors in the adult rat hippocampus,” Neuroscience, vol. 115, no. 2, pp. 515–524, 2002. View at Publisher · View at Google Scholar · View at Scopus
  80. X. Li, B. Z. Barkho, Y. Luo et al., “Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells,” Journal of Biological Chemistry, vol. 283, no. 41, pp. 27644–27652, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. K. E. Varley, J. Gertz, K. M. Bowling et al., “Dynamic DNA methylation across diverse human cell lines and tissues,” Genome Research, vol. 23, no. 3, pp. 555–567, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. G. Barreto, A. Schäfer, J. Marhold et al., “Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation,” Nature, vol. 445, no. 7128, pp. 671–675, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. J. Elder, M. Cortes, A. Rykman et al., “The epigenetics of stroke recovery and rehabilitation: from polycomb to histone deacetylases,” Neurotherapeutics, vol. 10, no. 4, pp. 808–816, 2013. View at Publisher · View at Google Scholar · View at Scopus
  84. H. Kassis, M. Chopp, X. S. Liu, A. Shehadah, C. Roberts, and Z. G. Zhang, “Histone deacetylase expression in white matter oligodendrocytes after stroke,” Neurochemistry International, vol. 77, pp. 17–23, 2014. View at Publisher · View at Google Scholar · View at Scopus
  85. M. Haberland, R. L. Montgomery, and E. N. Olson, “The many roles of histone deacetylases in development and physiology: implications for disease and therapy,” Nature Reviews Genetics, vol. 10, no. 1, pp. 32–42, 2009. View at Publisher · View at Google Scholar · View at Scopus
  86. B. Wang, X. Zhu, Y. Kim et al., “Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage,” Free Radical Biology & Medicine, vol. 52, no. 5, pp. 928–936, 2012. View at Publisher · View at Google Scholar · View at Scopus
  87. J. Hsieh, K. Nakashima, T. Kuwabara, E. Mejia, and F. H. Gage, “Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells,” Proceedings of the National Academy of Sciences, vol. 101, no. 47, pp. 16659–16664, 2004. View at Publisher · View at Google Scholar · View at Scopus
  88. Y. Shi, X. Zhao, J. Hsieh et al., “MicroRNA regulation of neural stem cells and neurogenesis,” Journal of Neuroscience, vol. 30, no. 45, pp. 14931–14936, 2010. View at Publisher · View at Google Scholar · View at Scopus
  89. J. Yang, X. Zhang, X. Chen, L. Wang, and G. Yang, “Exosome mediated delivery of miR-124 promotes neurogenesis after ischemia,” Molecular Therapy - Nucleic Acids, vol. 7, pp. 278–287, 2017. View at Publisher · View at Google Scholar · View at Scopus
  90. X. S. Liu, M. Chopp, R. L. Zhang et al., “MicroRNA profiling in subventricular zone after stroke: miR-124a regulates proliferation of neural progenitor cells through Notch signaling pathway,” PLoS One, vol. 6, no. 8, article e23461, 2011. View at Publisher · View at Google Scholar · View at Scopus
  91. S. E. Khoshnam, W. Winlow, Y. Farbood, H. F. Moghaddam, and M. Farzaneh, “Emerging roles of microRNAs in ischemic stroke: as possible therapeutic agents,” Journal of Stroke, vol. 19, no. 2, pp. 166–187, 2017. View at Publisher · View at Google Scholar · View at Scopus
  92. A. R. Filous and J. M. Schwab, “Determinants of axon growth, plasticity, and regeneration in the context of spinal cord injury,” The American Journal of Pathology, vol. 188, no. 1, pp. 53–62, 2018. View at Publisher · View at Google Scholar · View at Scopus
  93. S. T. Carmichael, “Rodent models of focal stroke: size, mechanism, and purpose,” NeuroRX, vol. 2, no. 3, pp. 396–409, 2005. View at Publisher · View at Google Scholar · View at Scopus
  94. D. Rabinovich, S. P. Yaniv, I. Alyagor, and O. Schuldiner, “Nitric oxide as a switching mechanism between axon degeneration and regrowth during developmental remodeling,” Cell, vol. 164, no. 1-2, pp. 170–182, 2016. View at Publisher · View at Google Scholar · View at Scopus
  95. I. E. Bonilla, K. Tanabe, and S. M. Strittmatter, “Small proline-rich repeat protein 1A is expressed by axotomized neurons and promotes axonal outgrowth,” The Journal of Neuroscience, vol. 22, no. 4, pp. 1303–1315, 2002. View at Publisher · View at Google Scholar
  96. R. J. Felling and H. Song, “Epigenetic mechanisms of neuroplasticity and the implications for stroke recovery,” Experimental Neurology, vol. 268, pp. 37–45, 2015. View at Publisher · View at Google Scholar · View at Scopus
  97. R. P. Simon, “Epigenetic modulation of gene expression governs the brain’s response to injury,” Neuroscience Letters, vol. 625, pp. 16–19, 2016. View at Publisher · View at Google Scholar · View at Scopus
  98. L. I. Benowitz and A. Routtenberg, “GAP-43: an intrinsic determinant of neuronal development and plasticity,” Trends in Neurosciences, vol. 20, no. 2, pp. 84–91, 1997. View at Publisher · View at Google Scholar · View at Scopus
  99. J. Skene, R. Jacobson, G. Snipes, C. McGuire, J. Norden, and J. Freeman, “A protein induced during nerve growth (GAP-43) is a major component of growth-cone membranes,” Science, vol. 233, no. 4765, pp. 783–786, 1986. View at Publisher · View at Google Scholar · View at Scopus
  100. P. X. Yuan, L. D. Huang, Y. M. Jiang, J. S. Gutkind, H. K. Manji, and G. Chen, “The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth,” Journal of Biological Chemistry, vol. 276, no. 34, pp. 31674–31683, 2001. View at Publisher · View at Google Scholar · View at Scopus
  101. H. Chiu, A. Alqadah, and C. Chang, “The role of microRNAs in regulating neuronal connectivity,” Frontiers in Cellular Neuroscience, vol. 7, 2014. View at Publisher · View at Google Scholar · View at Scopus
  102. B. Buller, M. Chopp, Y. Ueno et al., “Regulation of serum response factor by miRNA-200 and miRNA-9 modulates oligodendrocyte progenitor cell differentiation,” Glia, vol. 60, no. 12, pp. 1906–1914, 2012. View at Publisher · View at Google Scholar · View at Scopus
  103. F. Dajas-Bailador, B. Bonev, P. Garcez, P. Stanley, F. Guillemot, and N. Papalopulu, “MicroRNA-9 regulates axon extension and branching by targeting Map1b in mouse cortical neurons,” Nature Neuroscience, vol. 15, no. 5, pp. 697–699, 2012. View at Publisher · View at Google Scholar · View at Scopus
  104. J. Medin, J. Barajas, and K. Ekberg, “Stroke patients’ experiences of return to work,” Disability and Rehabilitation, vol. 28, no. 17, pp. 1051–1060, 2006. View at Publisher · View at Google Scholar · View at Scopus
  105. C. M. Stinear, W. D. Byblow, and S. H. Ward, “An update on predicting motor recovery after stroke,” Annals of Physical and Rehabilitation Medicine, vol. 57, no. 8, pp. 489–498, 2014. View at Publisher · View at Google Scholar · View at Scopus
  106. C. Dettmers, U. Teske, F. Hamzei, G. Uswatte, E. Taub, and C. Weiller, “Distributed form of constraint-induced movement therapy improves functional outcome and quality of life after stroke,” Archives of Physical Medicine and Rehabilitation, vol. 86, no. 2, pp. 204–209, 2005. View at Publisher · View at Google Scholar · View at Scopus
  107. J. Liepert, H. Bauder, W. H. R. Miltner, E. Taub, and C. Weiller, “Treatment-induced cortical reorganization after stroke in humans,” Stroke, vol. 31, no. 6, pp. 1210–1216, 2000. View at Publisher · View at Google Scholar · View at Scopus
  108. J. C. Stewart and S. C. Cramer, “Genetic variation and neuroplasticity: role in rehabilitation after stroke,” Journal of Neurologic Physical Therapy, vol. 41, Supplement 3, pp. S17–S23, 2017. View at Publisher · View at Google Scholar · View at Scopus
  109. H. Woldag and H. Hummelsheim, “Evidence-based physiotherapeutic concepts for improving arm and hand function in stroke patients,” Journal of Neurology, vol. 249, no. 5, pp. 518–528, 2002. View at Publisher · View at Google Scholar · View at Scopus
  110. J. A. Colombo, H. D. Reisin, J. J. Miguel-Hidalgo, and G. Rajkowska, “Cerebral cortex astroglia and the brain of a genius: a propos of A. Einstein’s,” Brain Research Reviews, vol. 52, no. 2, pp. 257–263, 2006. View at Publisher · View at Google Scholar · View at Scopus
  111. N. S. Ward and L. G. Cohen, “Mechanisms underlying recovery of motor function after stroke,” Archives of Neurology, vol. 61, no. 12, 2004. View at Publisher · View at Google Scholar · View at Scopus
  112. J. Classen, J. Liepert, S. P. Wise, M. Hallett, and L. G. Cohen, “Rapid plasticity of human cortical movement representation induced by practice,” Journal of Neurophysiology, vol. 79, no. 2, pp. 1117–1123, 1998. View at Publisher · View at Google Scholar · View at Scopus
  113. S. R. Belagaje, “Stroke rehabilitation 2017,” Cerebrovascular Disease, pp. 238–253, 2017. View at Google Scholar
  114. C. Seneviratne and M. Reimer, “Neurodevelopmental treatment stroke rehabilitation: a critique and extension for neuroscience nursing practice,” Axone, vol. 26, no. 2, pp. 13–20, 2004. View at Google Scholar
  115. F. Mu, D. Hurley, K. A. Betts et al., “Real-world costs of ischemic stroke by discharge status,” Current Medical Research and Opinion, vol. 33, no. 2, pp. 371–378, 2017. View at Publisher · View at Google Scholar · View at Scopus
  116. B. M. Kissela, J. C. Khoury, K. Alwell et al., “Age at stroke: temporal trends in stroke incidence in a large, biracial population,” Neurology, vol. 79, no. 17, pp. 1781–1887, 2012. View at Google Scholar
  117. M. K. Kapral, A. Laupacis, S. J. Phillips et al., “Stroke care delivery in institutions participating in the Registry of the Canadian Stroke Network,” Stroke, vol. 35, no. 7, pp. 1756–1762, 2004. View at Publisher · View at Google Scholar · View at Scopus
  118. E. Westerlind, H. C. Persson, and K. S. Sunnerhagen, “Return to work after a stroke in working age persons; a six-year follow up,” PLoS One, vol. 12, no. 1, article e0169759, 2017. View at Publisher · View at Google Scholar · View at Scopus
  119. S. Krishnan, M. R. Pappadis, S. C. Weller et al., “Needs of stroke survivors as perceived by their caregivers: a scoping review,” American Journal of Physical Medicine & Rehabilitation, vol. 96, no. 7, pp. 487–505, 2017. View at Publisher · View at Google Scholar · View at Scopus
  120. K. R. Brittain and C. Shaw, “The social consequences of living with and dealing with incontinence--a carers perspective,” Social Science & Medicine, vol. 65, no. 6, pp. 1274–1283, 2007. View at Publisher · View at Google Scholar · View at Scopus
  121. S. E. MacPherson, C. Healy, M. Allerhand et al., “Cognitive reserve and cognitive performance of patients with focal frontal lesions,” Neuropsychologia, vol. 96, pp. 19–28, 2017. View at Publisher · View at Google Scholar · View at Scopus
  122. M. Liguz-Lecznar and M. Kossut, “Influence of inflammation on poststroke plasticity,” Neural Plasticity, vol. 2013, Article ID 258582, 9 pages, 2013. View at Publisher · View at Google Scholar
  123. V. L. Feigin, B. Norrving, and G. A. Mensah, “Global burden of stroke,” Circulation Research, vol. 120, no. 3, pp. 439–448, 2017. View at Publisher · View at Google Scholar · View at Scopus