Remarkable cell recovery from cerebral ischemia in rats using an adaptive escalator-based rehabilitation mechanism

Autoři: Chi-Chun Chen aff001;  Yu-Lin Wang aff002;  Ching-Ping Chang aff005
Působiště autorů: Department of Electronic Engineering, National Chin-Yi University of Technology, Taichung, Taiwan aff001;  Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan aff002;  Center of General Education, Southern Taiwan University of Science and Technology, Tainan, Taiwan aff003;  Department of Physical Medicine and Rehabilitation, Chi Mei Medical Center, Tainan, Taiwan aff004;  Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223820


Currently, many ischemic stroke patients worldwide suffer from physical and mental impairments, and thus have a low quality of life. However, although rehabilitation is acknowledged as an effective way to recover patients’ health, there does not exist yet an adaptive training platform for animal tests so far. For this sake, this paper aims to develop an adaptive escalator (AE) for rehabilitation of rats with cerebral ischemia. Rats were observed to climb upward spontaneously, and a motor-driven escalator, equipped with a position detection feature and an acceleration/deceleration mechanism, was constructed accordingly as an adaptive training platform. The rehabilitation performance was subsequently rated using an incline test, a rotarod test, the infarction volume, the lesion volume, the number of MAP2 positive cells and the level of cortisol. This paper is presented in 3 parts as follows. Part 1 refers to the escalator mechanism design, part 2 describes the adaptive ladder-climbing rehabilitation mechanism, and part 3 discusses the validation of an ischemic stroke model. As it turned out, a rehabilitated group using this training platform, designated as the AE group, significantly outperformed a control counterpart in terms of a rotarod test. After the sacrifice of the rats, the AE group gave an average infarction volume of (34.36 ± 3.8)%, while the control group gave (66.41 ± 3.1)%, validating the outperformance of the escalator-based rehabilitation platform in a sense. An obvious difference between the presented training platform and conventional counterparts is the platform mechanism, and for the first time in the literature rats can be well and voluntarily rehabilitated at full capacity using an adaptive escalator. Taking into account the physical diversity among rats, the training strength provided was made adaptive as a reliable way to eliminate workout or secondary injury. Accordingly, more convincing arguments can be made using this mental stress-free training platform.

Klíčová slova:

Adaptive training – Animal performance – Cortisol – Ischemic stroke – Running – Surgical and invasive medical procedures – Neostriatum – Infarction


1. Smith HK, Russell JM, Granger DN, Gavins FNE. Critical differences between two classical surgical approaches for middle cerebral artery occlusion-induced stroke in mice. Journal of Neuroscience Methods. 2015; 249: 99–105. doi: 10.1016/j.jneumeth.2015.04.008 25936850

2. Lohse K, Bland MD, Lang CE. Quantifying change during outpatient stroke rehabilitation: a retrospective regression analysis. Archives of Physical Medicine and Rehabilitation. 2016; 97: 1423–1430. doi: 10.1016/j.apmr.2016.03.021 27109329

3. Hatem SM, Saussez G, della Faille M, Prist V, Zhang X, Dispa D, et al. Rehabilitation of motor function after stroke: a multiple systematic review focused on techniques to stimulate upper extremity recovery. Frontiers in Human Neuroscience. 2016; 10: 442. doi: 10.3389/fnhum.2016.00442 27679565

4. Livingston-Thomas J, Nelson P, Karthikeyan S, Antonescu S, Jeffers MS, Marzolini S, et al. Exercise and environmental enrichment as enablers of task-specific neuroplasticity and stroke recovery. Neurotherapeutics. 2016; 13: 395–402. doi: 10.1007/s13311-016-0423-9 26868018

5. Pin-Barre C, Laurin J. Physical exercise as a diagnostic, rehabilitation, and preventive tool: influence on neuroplasticity and motor recovery after stroke. Neural Plasticity. 2015; 2015:608581. doi: 10.1155/2015/608581 26682073

6. Zheng HQ, Zhang LY, Luo J, Li LL, Li ML, Zhang Q, et al. Physical exercise promotes recovery of neurological function after ischemic stroke in rats. International Journal of Molecular Sciences. 2014; 15: 10974–10988. doi: 10.3390/ijms150610974 24945308

7. Ding Y, Li J, Luan X, Ding YH, Lai Q, Rafols JA, et al. Exercise pre-conditioning reduces brain damage in ischemic rats that may be associated with regional angiogenesis and cellular overexpression of neurotrophin. Neuroscience. 2004; 124: 583–591. doi: 10.1016/j.neuroscience.2003.12.029 14980729

8. Wang RY, Yang YR, Yu SM. Protective effects of treadmill training on infarction in rats. Brain Research. 2001; 922: 140–143. doi: 10.1016/s0006-8993(01)03154-7 11730712

9. Ke Z, Yip SP, Li L, Zheng XX, Tong KY. The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: a rat brain ischemia model. Plos One. 2011; 6: e16643. doi: 10.1371/journal.pone.0016643 21347437

10. Ploughman M, Granter-Button S, Chernenko G, Attwood Z, Tucker BA, Mearow KM, et al. Exercise intensity influences the temporal profile of growth factors involved in neuronal plasticity following focal ischemia. Brain Research. 2007; 1150: 207–216. doi: 10.1016/j.brainres.2007.02.065 17382914

11. Ploughman M, Granter-Button S, Chernenko G, Tucker BA, Mearow KM, Corbett D. Endurance exercise regimens induce differential effects on brain-derived neurotrophic factor, synapsin-I and insulin-like growth factor I after focal ischemia. Neuroscience. 2005; 136: 991–1001. doi: 10.1016/j.neuroscience.2005.08.037 16203102

12. Dominici N, Keller U, Vallery H, Friedli L, van den Brand R, Starkey ML, et al. Versatile robotic interface to evaluate, enable and train locomotion and balance after neuromotor disorders. Nature Medicine. 2012; 18: 1142–7. doi: 10.1038/nm.2845 22653117

13. Udoekwere UI, Oza CS, Giszter SF. Teaching adult rats spinalized as neonates to walk using trunk robotic rehabilitation: elements of success, failure, and dependence. Journal of Neuroscience. 2016; 36: 8341–8355. doi: 10.1523/JNEUROSCI.2435-14.2016 27511008

14. Stoller O, de Bruin ED, Schindelholz M, Schuster-Amft C, de Bie RA, Hunt KJ. Efficacy of feedback-controlled robotics-assisted treadmill exercise to improve cardiovascular fitness early after stroke: a randomized controlled pilot trial. journal of neurologic physical therapy. 2015; 39: 156–165. doi: 10.1097/NPT.0000000000000095 26050073

15. Hayes K, Sprague S, Guo M, Davis W, Friedman A, Kumar A, et al. Forced, not voluntary, exercise effectively induces neuroprotection in stroke. Acta Neuropathologica. 2008; 115: 289–296. doi: 10.1007/s00401-008-0340-z 18210137

16. Brown DA, Johnson MS, Armstrong CJ, Lynch JM, Caruso NM, Ehlers LB, et al. Short-term treadmill running in the rat: what kind of stressor is it? Journal of Applied Physiology. 2007; 103: 1979–1985. doi: 10.1152/japplphysiol.00706.2007 17916671

17. Moraska A, Deak T, Spencer RL, Roth D, Fleshner M. Treadmill running produces both positive and negative physiological adaptations in Sprague-Dawley rats. American Journal of Physiology-Regulatory Integrative and Comparative Physiology. 2000; 279: R1321–R1329.

18. Frasier CR, Moore RL, Brown DA. Exercise-induced cardiac preconditioning: how exercise protects your achy-breaky heart. Journal of Applied Physiology. 2011; 111: 905–915. doi: 10.1152/japplphysiol.00004.2011 21393468

19. Peng CW, Chen SC, Lai CH, Chen CJ, Chen CC, Mizrahi J, et al. Review: clinical benefits of functional electrical stimulation cycling exercise for subjects with central neurological impairments. Journal of Medical and Biological Engineering. 2011; 31: 1–11.

20. Chen CC, Chang MW, Chang CP, Chan SC, Chang WY, Yang CL, et al. A forced running wheel system with a microcontroller that provides high-intensity exercise training in an animal ischemic stroke model. Brazilian Journal of Medical and Biological Research. 2014; 47: 858–868. doi: 10.1590/1414-431X20143754 25140816

21. Kennard JA, Woodruff-Pak DS. A comparison of low- and high-impact forced exercise: Effects of training paradigm on learning and memory. Physiology & Behavior. 2012; 106: 423–427.

22. Leasure JL, Jones M. Forced and voluntary exercise differentially affect brain and behavior. Neuroscience. 2008; 156: 456–465. doi: 10.1016/j.neuroscience.2008.07.041 18721864

23. Waters RP, Renner KJ, Pringle RB, Summers CH, Britton SL, Koch LG, et al. Selection for aerobic capacity affects corticosterone, monoamines and wheel-running activity. Physiology & Behavior. 2008; 93: 1044–1054.

24. Fantegrossi WE, Xiao WR, Zimmerman SM. Novel technology for modulating locomotor activity as an operant response in the mouse: implications for neuroscience studies involving “exercise” in rodents. Journal of Neuroscience Methods. 2013; 212: 338–343. doi: 10.1016/j.jneumeth.2012.10.020 23164960

25. Yang YR, Wang RY, Wang PS, Yu SM. Treadmill training effects on neurological outcome after middle cerebral artery occlusion in rats. Canadian Journal of Neurological Sciences. 2003; 30: 252–258. doi: 10.1017/s0317167100002687 12945951

26. Soya H, Nakamura T, Deocaris CC, Kimpara A, Iimura M, Fujikawa T, et al. BDNF induction with mild exercise in the rat hippocampus. Biochemical and Biophysical Research Communications. 2007; 358: 961–967. doi: 10.1016/j.bbrc.2007.04.173 17524360

27. Schaaf MJM, de Jong J, de Kloet ER, Vreugdenhil E. Downregulation of BDNF mRNA and protein in the rat hippocampus by corticosterone. Brain Research. 1998; 813: 112–120. doi: 10.1016/s0006-8993(98)01010-5 9824681

28. Vilela TC, Effting PS, Dos Santos Pedroso G, Farias H, Paganini L, Rebelo Sorato H, et al. Aerobic and strength training induce changes in oxidative stress parameters and elicit modifications of various cellular components in skeletal muscle of aged rats. Exp Gerontol. 2018; 106: 21–27. doi: 10.1016/j.exger.2018.02.014 29471131

29. Docherty D, Sporer B. A proposed model for examining the interference phenomenon between concurrent aerobic and strength training. Sports Med. 2007; 30: 385–394.

30. Jung S, Ahn N, Kim S, Byun J, Joo Y, Kim S, et al. The effect of ladder-climbing exercise on atrophy/hypertrophy-related myokine expression in middle-aged male Wistar rats. Journal of Physiological Sciences. 2015; 65: 515–521. doi: 10.1007/s12576-015-0388-1 26223833

31. Neves RVP, Souza MK, Passos CS, Bacurau RFP, Simoes HG, Prestes J, et al. Resistance training in spontaneously hypertensive rats with severe hypertension. Arquivos Brasileiros De Cardiologia. 2016; 106: 201–209. doi: 10.5935/abc.20160019 26840054

32. Pin-Barre C, Laurin J, Felix MS, Pertici V, Kober F, Marqueste T, et al. Acute neuromuscular adaptation at the spinal level following middle cerebral artery occlusion-reperfusion in the rat. Plos One. 2014; 9: e89953. doi: 10.1371/journal.pone.0089953 24587147

33. Tang L, Gao X, Yang X, Liu C, Wang X, Han Y, et al. Ladder-climbing training prevents bone loss and microarchitecture deterioration in diet-induced obese rats. Calcified Tissue International. 2016; 98: 85–93. doi: 10.1007/s00223-015-0063-9 26410845

34. Lin W, Hsuan YC, Lin MT, Kuo TW, Lin CH, Su YC, et al. Human umbilical cord mesenchymal stem cells preserve adult newborn neurons and reduce neurological injury after cerebral ischemia by reducing the number of hypertrophic microglia/macrophages. Cell Transplant. 2017; 26: 1798–1801. doi: 10.1177/0963689717728936 29338384

35. Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989; 20: 84–91. doi: 10.1161/01.str.20.1.84 2643202

36. Chang MW, Young MS, Lin MT. An inclined plane system with microcontroller to determine limb motor function of laboratory animals. Journal of Neuroscience Methods. 2008; 168: 186–194. doi: 10.1016/j.jneumeth.2007.09.013 17953994

37. Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke. 2001; 32: 1005–1011. doi: 10.1161/01.str.32.4.1005 11283404

38. Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR. A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab. 1990; 10: 290–293. doi: 10.1038/jcbfm.1990.47 1689322

39. Zhu J, Liu K, Huang K, Gu Y, Hu Y, Pan S, et al. Metformin improves neurologic outcome via amp‐activated protein kinase–mediated autophagy activation in a rat model of cardiac arrest and resuscitation. J Am Heart Assoc. 2018; 7: e008389. doi: 10.1161/JAHA.117.008389 29895585

40. Dawson DA, Hallenbeck JM. Acute focal ischemia-induced alterations in MAP2 immunostaining: description of temporal changes and utilization as a marker for volumetric assessment of acute brain injury. J Cereb Blood Flow Metab. 1996; 16: 170–174. doi: 10.1097/00004647-199601000-00020 8530550

41. Zhao S, Wang X, Gao X, Chen J. Delayed and progressive damages to juvenile mice after moderate traumatic brain injury. Sci Rep. 2018; 8: 7339. doi: 10.1038/s41598-018-25475-9 29743575

42. Villapol S, Byrnes KR, Symes AJ. Temporal dynamics of cerebral blood flow, cortical damage, apoptosis, astrocyte–vasculature interaction and astrogliosis in the pericontusional region after traumatic brain injury. Front Neurol. 2014; 5: 82. doi: 10.3389/fneur.2014.00082 24926283

43. Zille M, Farr TD, Przesdzing I, Müller J, Sommer C, Dirnagl U, et al. Visualizing cell death in experimental focal cerebral ischemia: promises, problems, and perspectives. J Cereb Blood Flow Metab. 2012; 32: 213–231. doi: 10.1038/jcbfm.2011.150 22086195

44. Lee MY, Chang PH, Kwon YH, Jang SH. Differences of the frontal activation patterns by finger and toe movements: a functional MRI study. Neuroscience Letters. 2013; 533: 7–10. doi: 10.1016/j.neulet.2012.11.041 23206749

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