REVIEW ARTICLE

Neuroregeneration, neurodegeneration and brain recovery following ischaemic stroke: a comparative review of animal models and humans

Mathangasinghe Y1 1Department of Anatomy, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka

Abstract Main Article

Stroke is a leading cause of healthcare Stroke is defined as an acute brain insult burden in the aging population with a due to a vascular event leading to rapidly rising prevalence worldwide. permanent injury to neurones and Ischaemic strokes account for 85% of the functional compromise [1]. Strokes are strokes. The key to recovery of brain caused by inadequate blood supply to the functions following an ischaemic stroke brain to meet its metabolic demands. depends on two arms: 1) restoration of They can be classified into two major sub lost or damaged neurones and, 2) groups based on the pathophysiology: survival of neurones that were not killed ischaemic and haemorrhagic. Ischaemic by the injury. Hence, the recovery could strokes occur usually secondary to b e h a s t e n e d b y p r o m o t i n g occlusion of a cerebral blood vessel [1]. neuroregeneration and preventing Ischaemic strokes are by far the neurodegeneration. During the last five commonest type worldwide accounting decades, animal models showed for 85% of the strokes [1]. The Global promising results in the field of Burden of Disease study concluded that neuroregeneration, which was long ischaemic strokes account for 2 690 200 believed to be impossible. Furthermore, deaths in the world in 2016 [2]. The animal studies with stroke lead to the incidence of stroke in Asia is 116 to 483 discovery of the novel concepts of per 100 000 per year [3]. epigenetic inhibition in growth, upregulation of apoptotic genes, Mechanisms of recovery from ischaemic neuroinflammation and metabolic stroke dysregulation which contributed to neurodegeneration. However, it is The key to recovery of function debatable if these findings can be following a stroke depend on two arms: replicated in human brains, in order to 1) restoration of lost or damaged develop potential therapeutic strategies. neurones and, 2.) survival of neurones that were killed by the injury. The mechanism of restoration of the lost or Keywords damaged neurones is by means of repair stroke, nerve , nerve and regeneration. The repair of damaged degeneration, long within the central is markedly limited, particularly

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Mathangasinghe Y - Neuroregeneration, neurodegeneration and brain recovery following ischaemic stroke: a comparative review of animal models and humans due to the active inhibition of axonal proves that understanding of the regrowth by the glial cells [4]. mechanism of adult neurogenesis is far Conversely, the belief of inability of from clear. neurones to regenerate was challenged in S i m i l a r l y, t h e m e c h a n i s m o f recent studies. neuroregeneration following ischaemic stroke is poorly understood. A few Neuroregeneration studies investigated the patterns of Altman in 1962 first described the neuroregeneration following a stroke. neurogenesis in adult mammalian brain Radiocarbon-14 dating studies failed to [5]. In 1998, Eriksson and colleagues show neuroregeneration in forebrain found that the neurogenesis happens in following stroke [21], whereas the dentate gyrus of the adult human i m m u n o c y t o l o g i c a l s t u d i e s hippocampus [6]. Adult hippocampal demonstrated a possible neurogenesis neurogenesis declines with aging in with migratory phenotype [22-24]. Few rodents [7] and non-human primates [8]. in vitro and in vivo studies elicited that There are striking differences of the neurogenesis is co-regulated with neurogenesis between humans and angiogenesis [25-28]. An age associated animals. Neuronal migration from decline in both angiogenesis and subventricular zone to olfactory bulb neuronal plasticity was found in a human along the rostral migratory system could study [20]. However, correlations of only be demonstrated in rodent [9, 10] neuroregeneration and angiogenesis in and non-human primate [11, 12] studies. humans are not reported. Whereas, unique features like striatal neurogenesis was not demonstrated in Neurodegeneration animal studies [13, 14]. Likewise, there Ischaemic damage to the brain initiates a is conflicting evidence whether cascade of events which leads to death of neurogenesis happens in the normal partially injured neurones leading to a d u l t b r a i n s [ 1 5 - 1 8 ] . U s i n g neurodegeneration. Transcriptomic immunofluorescence staining, Sorrells analyses of ischaemic penumbra of rats and colleagues concluded that provided insight into temporal neurogenesis in humans rapidly declines relationship of differential expression of from 7 to 13 years of age and it is almost genes responsible for metabolic, non-existent in the adult age [19]. inflammatory and immunological Despite adapting a fairly similar p a t h w a y s i n p o s t - i s c h a e m i c methodology, Boldrini and colleagues neurodegeneration [29]. Subsequent found that the neurogenesis persists in animal studies with stroke lead to the adult even until the eighth discovery of the novel concepts of decade of life, even though the quiescent epigenetic inhibition of axonal sprouting neural stem population, neural [30], extensive upregulation of apoptotic plasticity and angiogenesis declines with genes [29], neuroinflammation [31] and aging process [20]. The contrasting metabolic dysregulation [32]. However, evidence by these two landmark studies genes which prevent inflammation [33,

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Mathangasinghe Y - Neuroregeneration, neurodegeneration and brain recovery following ischaemic stroke: a comparative review of animal models and humans

34] and oxidative stress [35] after 4. Yiu, G. and Z. He, Glial inhibition of ischaemic stroke were also discovered. CNS regeneration. Nature Nevertheless, controversial results Reviews Neuroscience, 2006. 7(8): against the and gene fusion p. 617. following stroke were found in a human 5. Altman, J., Are new formed study [21]. in the brains of adult mammals? Science, 1962. 135(3509): p. 1127- Conclusions 1128. Nerve regeneration and degeneration 6. Eriksson, P.S., et al., Neurogenesis in may play a critical role in the recovery of the adult human hippocampus. 1998. stroke. However, we cannot ascribe the 4(11): p. 1313. results of neuroregeneration and 7. B e n A b d a l l a h , N . M . B . , L . neurodegeneration found in animal S l o m i a n k a , a n d H . P. L i p p , models directly to humans. Human Reversible effect of X‐irradiation on studies are scarce due to lack of access to proliferation, neurogenesis, and cell tissues and technical problems of tissue death in the dentate gyrus of adult handling and sequencing. Therefore, mice. Hippocampus, 2007. 17(12): p. there are ambiguities and gaps in 1230-1240. knowledge of the dynamic balance 8. Leuner, B., et al., Diminished adult between protective and damaging neurogenesis in the marmoset brain factors leading to post-ischaemic precedes old age. Proceedings of the n e u r o r e g e n e r a t i o n a n d National Academy of Sciences, neurodegeneration in humans. 2007. 104(43): p. 17169-17173. 9. Lois, C. and A. Alvarez-Buylla, References Long-distance neuronal migration in the adult mammalian brain. Science, 1. Miller, C.M., Stroke Epidemiology, 1994. 264(5162): p. 1145-1148. in Translational Research in Stroke. 10. L u s k i n , M . B . , R e s t r i c t e d 2017, Springer. p. 41-49. proliferation and migration of 2. Naghavi, M., et al., Global, regional, postnatally generated neurons and national age-sex specific d e r i v e d f ro m t h e f o re b r a i n mortality for 264 causes of death, subventricular zone. , 1993. 1980–2016: a systematic analysis for 11(1): p. 173-189. the Global Burden of Disease Study 11. Bédard, A., et al., The rostral 2016. The Lancet, 2017. 390(10100): migratory stream in adult squirrel p. 1151-1210. monkeys: contribution of new 3. S u w a n w e l a , N . C . a n d N . neurons to the olfactory tubercle and Poungvarin, Stroke burden and involvement of the antiapoptotic s t ro k e c a re s y s t e m i n A s i a . protein Bcl‐2. European Journal of Neurology India, 2016. 64(7): p. 46. Neuroscience, 2002. 16(10): p. 1917-1924.

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Mathangasinghe Y - Neuroregeneration, neurodegeneration and brain recovery following ischaemic stroke: a comparative review of animal models and humans

12. Kornack, D.R. and P. Rakic, The 20. Boldrini, M., et al., Human g e n e r a t i o n , m i g r a t i o n , a n d hippocampal neurogenesis persists differentiation of olfactory neurons throughout aging. Cell Stem Cell, in the adult pr im ate br ain. 2018. 22(4): p. 589-599. e5. Proceedings of the National 21. Huttner, H.B., et al., The age and Academy of Sciences, 2001. 98(8): genomic integrity of neurons after p. 4752-4757. cortical stroke in humans. Nature 13. Bergmann, O., K.L. Spalding, and J. neuroscience, 2014. 17(6): p. 801. Frisén, Adult neurogenesis in 22. Jin, K., et al., Evidence for stroke- humans. Cold Spring Harbor induced neurogenesis in the human perspectives in biology, 2015. 7(7): brain. Proceedings of the National p. a018994. Academy of Sciences, 2006. 14. Ernst, A., et al., Neurogenesis in the 103(35): p. 13198-13202. striatum of the adult human brain. 23. M a r t i - F a b r e g a s , J . , e t a l . , Cell, 2014. 156(5): p. 1072-1083. P ro l i f e r a t i o n i n t h e h u m a n 15. Bédard, A. and A. Parent, Evidence of ipsilateral subventricular zone after newly generated neurons in the ischemic stroke. 2010. 74(5): p. 357- h u m a n o l f a c t o r y b u l b . 365. Developmental brain research, 2004. 24. Macas, J., et al., Increased 151(1-2): p. 159-168. generation of neuronal progenitors 16. Bergmann, O., et al., The age of after ischemic injury in the aged olfactory bulb neurons in humans. adult human forebrain. Journal of Neuron, 2012. 74(4): p. 634-639. Neuroscience, 2006. 26(50): p. 17. Quiñones‐Hinojosa, A., et al., 13114-13119. C e l l u l a r c o m p o s i t i o n a n d 25. Boldrini, M., et al., Hippocampal cytoarchitecture of the adult human angiogenesis and progenitor cell subventricular zone: a niche of proliferation are increased with neural stem cells. Journal of antidepressant use in major Comparative Neurology, 2006. depression. Biological psychiatry, 494(3): p. 415-434. 2012. 72(7): p. 562-571. 18. Nogueira, A.B., et al., Existence of a 26. Heine, V.M., et al., Chronic stress in potential neurogenic system in the the adult dentate gyrus reduces cell adult human brain. Journal of proliferation near the vasculature translational medicine, 2014. 12(1): and VEGF and Flk‐1 protein p. 75. expression. European Journal of 19. Sorrells, S.F., et al., Human Neuroscience, 2005. 21(5): p. 1304- hippocampal neurogenesis drops 1314. sharply in children to undetectable 27. Warner-Schmidt, J.L. and R.S. levels in adults. Nature, 2018. Duman, VEGF is an essential 555(7696): p. 377. mediator of the neurogenic and

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Mathangasinghe Y - Neuroregeneration, neurodegeneration and brain recovery following ischaemic stroke: a comparative review of animal models and humans

b e h a v i o r a l a c t i o n s o f C l i n i c a l a n d E x p e r i m e n t a l antidepressants. Proceedings of the Pharmacology and Physiology, National Academy of Sciences, 2007. 34(11): p. 1097-1101. 2007. 104(11): p. 4647-4652. 34. Shichita, T., et al., MAFB prevents 28. Thored, P.r., et al., Long-term excess inflammation after ischemic neuroblast migration along blood stroke by accelerating clearance of vessels in an area with transient damage signals through MSR1. angiogenesis and increased Nature medicine, 2017. 23(6): p. vascularization after stroke. Stroke, 723. 2007. 38(11): p. 3032-3039. 35. Belayev, L., et al., Neuroprotectin D1 29. Lu, A., et al., Genomics of the upregulates Iduna expression and periinfarction cortex after focal provides protection in cellular cerebral ischemia. Journal of uncompensated oxidative stress and Cerebral Blood Flow & Metabolism, in experimental ischemic stroke. Cell 2003. 23(7): p. 786-810. death and differentiation, 2017. 30. Li, S., et al., An age-related sprouting 24(6): p. 1091. transcriptome provides molecular control of axonal sprouting after Conflicts of Interests stroke. Nature neuroscience, 2010. 13(12): p. 1496. The authors declare that there are no 31. Schmidt-Kastner, R., et al., DNA conflicts of interests. microarray analysis of cortical gene e x p r e s s i o n d u r i n g e a r l y recirculation after focal brain ischemia in rat. Molecular Brain Research, 2002. 108(1-2): p. 81-93. 32. Barteczek, P., et al., Neuronal HIF- 1α and HIF-2α deficiency improves neuronal survival and sensorimotor function in the early acute phase after ischemic stroke. Journal of Cerebral Blood Flow & Metabolism, 2017. 37(1): p. 291-306. 33. Sun, S.L., et al., Modulation of signal transducers and activators of transcription (STAT) factor pathways during focal cerebral ischaemia: a gene expression array study in rat hippocampus after middle cerebral artery occlusion.

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