Brain Injury

ISSN: 0269-9052 (Print) 1362-301X (Online) Journal homepage: http://www.tandfonline.com/loi/ibij20

Differential impact of treadmill training on strokeinduced neurological disorders Rasoul Rezaei, Maryam Nourshahi, Fariba Khodagholi, Abbas Haghparast, Sanaz Nasoohi, Mohammadreza Bigdeli & Ghorbangol Ashabi To cite this article: Rasoul Rezaei, Maryam Nourshahi, Fariba Khodagholi, Abbas Haghparast, Sanaz Nasoohi, Mohammadreza Bigdeli & Ghorbangol Ashabi (2017): Differential impact of treadmill training on stroke-induced neurological disorders, Brain Injury, DOI: 10.1080/02699052.2017.1346287 To link to this article: http://dx.doi.org/10.1080/02699052.2017.1346287

Published online: 12 Sep 2017.

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Date: 17 September 2017, At: 10:06

BRAIN INJURY https://doi.org/10.1080/02699052.2017.1346287

Differential impact of treadmill training on stroke-induced neurological disorders Rasoul Rezaeia, Maryam Nourshahia, Fariba Khodagholib, Abbas Haghparastb, Sanaz Nasoohib, Mohammadreza Bigdelic, and Ghorbangol Ashabi*d a

Department of Sport Physiology, Faculty of Physical Education and Sport Sciences, Shahid Beheshti University, G.C., Evin 198396113, Tehran, Iran; Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; cFaculty of Biological Sciences, Shahid Beheshti University, G.C. Tehran, Iran; dDepartment of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

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b

ABSTRACT

ARTICLE HISTORY

Objective: Physical exercise contributes to improving stability against nerve injury caused by ischaemic stroke. Here we aimed to preliminarily investigate the effects of continuous endurance training (CET) and high-intensity interval training (HIT) on stroke-associated anxiety, locomotion, neurological assessments and P70S6 Kinase (P70S6K) activation as well. To do this, rats were trained according to HIT and CET protocols for 2 months prior to being subject to middle cerebral artery occlusion surgery. Methods: Twenty-four hours later behavioural examination was performed by elevated plus maze (EPM) testing, open field and neurological scoring followed by cortical and hippocampal P70S6Ks immunoblotting. Results: According to the obtained data pre-ischaemic HIT and CET similarly improved neurological performance, anxiety levels and locomotion in EPM and open field tests following ischaemic stroke while there was a remarkable rise in hippocampal and cortical P70S6K activation in the HIT group compared to the CET counterparts. Conclusion: Behavioral and molecular data suggest that interval training is more beneficial rather than CET, but the distinct mechanisms of CET and HIT on memory are still topics to be discovered.

Received 22 September 2016 Revised 18 March 2017 Accepted 19 June 2017 Published online 11 September 2017

Introduction Ischaemic stroke, being one of the most debilitating neurological injuries, imposes a serious burden on societies. The contribution of physical exercise preconditioning to efficient recovery following stroke has been demonstrated in improved stability against neural injury and enhanced neuronal viability and neurogenesis [1,2]. Such protective effects have been mainly ascribed to enhanced cerebral tropic molecules like brain-derived neurotrophic factor, nerve growth factor and neurotrophin-3 [3–6]. Among various types of physical practices, moderate continuous exercise has been empirically shown to efficiently increase cell proliferation and reduce infarct size in ischaemic stroke [7,8]. However, based on the emerging trend towards less time-consuming activities [9], many investigations are focusing on the alleviating impact of high-intensity interval training (HIT) against neurological damages [10–12]. Accordingly, HIT seems to provide protection against neural injury probably through enhanced neuroprotective effectors like heat shock protein or insulin signaling pathway [11,13], although there are some controversies with regard to specific advantageous effects of HIT against cerebral ischaemia as compared to continuous endurance training (CET). The present experiments are basically designed to address the differential impact of CET and HIT on functional and physiological outcomes of occlusive stroke in rats as simulated by two types of treadmill pre-training. Additionally, there are CONTACT Ghorbangol Ashabi Tehran, Iran © 2017 Taylor & Francis Group, LLC

[email protected]

KEYWORDS

Continuous endurance training; high-intensity training; P70S6Kinase; cerebral ischaemia

unclear data on the role of the mTOR (mammalian Target of Rapamycin) effector P70S6 Kinase (P70S6K) in neural injury despite its defined role in exercise impact on cardiac cells [14– 16]. Given there are also recent reports suggestive of P70S6K’s role in anxiety and depression in neuronal disorders [17,18], the corresponding changes in P70S6K activation were also detected in animals’ brain to explore probable associations with behavioural defects following ischaemic stroke.

Materials and methods Animals and training protocols Male Wistar rats (weighting 270–300 g at the beginning of experiments) were obtained from Pasteur institute (Tehran, Iran) and habituated to animals’ room in Plexiglas cage and maintained in a room with controlled light/dark cycle (12/12 hours with light beginning at 7:00 a.m.), at a temperature of 22 ± 2°C and food and water provided ad libitum. Maximum Oxygen consumption (VO2max) was determined based on maximum speed attained during a ramp running test as previously described by Leandro et al. Then, speeds corresponding to various percent’s of VO2max were used as different training intensity in the groups of the study. [19]. Animals in the CET group were run intermittently for 8 weeks at 40–50% speed of VO2 (5 minutes), at 70% speed corresponding at VO2max (30 minutes) and then at 40–50% a speed corresponding at VO2max (5 minutes). In the HIT

Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, P.O. box: 1417613151,

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group, animals were trained for 30 minutes a day for 3 days/ week for 8 weeks. Each training consisted of 40–50% speed corresponding at VO2max for 5 minutes (warm up) followed by a 30-minute intermittent high-intensity run (2 minutes) and low-intensity run (2 minutes) which was terminated with a 5minute run at 40–50% a speed corresponding at VO2max (cool down). The speed for the high-intensity run was first adjusted to 70% (first week) and then increased to 85% (secon.d week), 100% (third week) and 110 % (fourth to eighth weeks) a speed corresponding at VO2max while the speed of VO2 was 40% speed of VO2 low intensity which measured by ramp test. afterward, both groups run for five minutes in 40-50% a speed corresponding at VO2max for cool down. The trained groups performed the ramp protocol test every week and the intensity of training was determined by the new speed of ramp protocol test each week. All experimental procedures were approved by the Ethics Committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran, and were in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (ninth edition, 2010). All efforts were made to minimize the suffering of animals. Experimental design Forty-eight male rats were randomly divided into six groups: 1) sham surgery group, 2) Ischaemia/Reperfusion (I/R) group, 3) CET group which received CET only, 4) CET-I/R group which received I/R plus CET, 5) HIT group which received HIT only, 6) HIT-I/R group which received I/R plus HIT. There are no differences between the intact group and sham surgery group; therefore we represent the sham surgery group as ‘sham’ in the results section. We used eight rats for all behavioural tests and four rats for Western blotting technique. Middle cerebral artery occlusion (MCAO) Rats anaesthetized with chloral hydrate (400 mg/kg, i.p, Sigma Aldrich Co. St. Louis, USA) were subjected to MCAO by a silicone-coated monofilament [20]. Regional cerebral blood flow was monitored by laser Doppler flowmetry (MBF3D, Moor instrument, Axminster, UK) with use of a flexible fiberoptic probe fixed to the intact skull above the territory of the right Middle cerebral artery (MCA). Rectal temperature was maintained between 37°C and 38°C with a heating pad. After 90 minutes of occlusion and monofilament withdrawal, the neck wound was sutured and animals were allowed to recover from the anaesthesia [21]. Behavioural tests Neurological deficit evaluation Neurological evaluations were carried out 24 hours after I/R according to Garcia’s protocol [22]. Briefly the proprioception and sensorimotor activities were graded from 1 to 3 respectively according to animals’ reflexes to a blunt stick touching each side of the body or brushing the vibrissae (stick not entered to the animals’s visual field). The animals’ locomotion was also assessed by appraising the spontaneous activity, symmetry in

four limbs’ movement, forepaw outstretching and climbing on the wall of a wire cage (each item scored 0 to 3 score) Elevated plus maze (EPM) test The wooden apparatus consisting of two open and two closed arms (each 50 × 10 cm) with 40-cm-high side walls was positioned 50 cm above the floor [23]. Twenty-four hours after reperfusion, each animal was adapted to the test room for 1 hour and then placed in the centre of EPM with its head facing an open arm and left undisturbed for 5 minutes. The total time spent in the open arms [OAT% (the ratio of times spent in the open arms to total time spent in any arms × 100)] and the number of entries in open arms [OAE% (the ratio of entries into open arms to the total entries × 100)] were used as measures of anxiety [24,25]. Open field test The open field opaque acrylic box (50 × 50 × 40 cm) was placed in an isolated room with no objects or clues. The box floor was divided into 10 numbered squares, approximately 16 × 16 cm2 each in order to address central or parietal localization. Twentyfour hours after reperfusion each animal’s locomotion was tested for 5 minutes in the box with all movements recorded by a video camera mounted on the ceiling of the room (Maze router, Tabriz, Iran). Scoring was performed by both maze router analysis and manually, and expressed as ‘Moving distance (metres)’ and ‘Time spent in the central square (s)’ [24,25]. Western blot analysis Following animals’ euthanization and decapitation 24 hours post reperfusion, the cerebral cortices and hippocampi were dissected and flash frozen in liquid nitrogen and stored at −80°C. When ready for Western blotting all samples were homogenized in the appropriate lysis buffer [26] and the total protein extract was prepared by centrifugation at 15 000 rpm for 5 minutes. Standardized lysates equivalent to 60 µg of protein [27] were loaded on SDS-12.5% poly acrylamide gel electrophoresis, and transferred to a Polyvinylidene difluoride (PVDF) membrane (Chemicon Millipore Co. Temecula, USA). Then, blots were blocked in 2% Electrochemiluminescence advanced kit blocking reagent (Amersham Bioscience Co. Piscataway, USA) and probed with phosphorylated P70S6K and total P70S6K (1/1000, Cell Signaling Technology Co. New York, USA) antibodies overnight. Membranes were then incubated with rabbit IgG-horseradish peroxidase-conjugated secondary antibody (1/3000, Cell Signaling Technology Co. New York, USA) which was directly detected by a chemiluminescence kit reagent (Amersham Bioscience Co. Piscataway, USA). To detect β-actin as an internal control, blots were stripped in stripping buffer (pH = 6.7) and then probed with anti β-actin antibody (1/1000, Cell Signaling Technology Co. New York, USA) [26]. Statistical analysis All data were analysed by one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test for multiple comparisons, using SPSS ver. 16.0 package program. Data are expressed as mean ± SEM and statistical significance was set at p < 0.05.

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Results

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CET and HIT impacts on neurological performance following I/R injury Tukey’s post hoc test following one-way ANOVA showed a significant I/R injury in neurological scores based on Garcia’s testing (p < 0.001, Figure 1). Accordingly, while 2-month-long CET and HIT had no impact on neurological scores by itself, both were efficient enough to improve neurological scores following MCAO (p < 0.001 and p < 0.01, respectively). Furthermore, open field testing of total animals’ motility showed no significant changes between ischemic CET and HIT groups in total distance moved (Figure 2A). As is obvious from non-ischaemic groups, part of such improving effects could be ascribed to the protective impact of CET and HIT independent of the context of ischaemic injury. CET and HIT effects on stroke-induced anxiety Centre occupancy time in the open field test performed 24 hours post reperfusion demonstrated a remarkable improvement in CET-I/R and HIT-I/R groups compared with the I/R group (p < 0.001, Figure 2B). Also, there are no differences between the CET-I/R HIT-I/R groups in the centre occupancy time and travelled distances (p > 0.05, Figure 2A andB). Such effects, presumptively suggestive of anxiolytic effects of CET and HIT, were confirmed by EPM results. According to our results the percentage of open arm time and open arm entries increased in both the CET-I/R and HIT-I/R groups compared with the I/R group (p < 0.001, Figure 3A and 3B). Interestingly, CET and HIT showed a similar and significant enhancement in percentage of open arm time and open arm entries in intact animals (p < 0.05). CET and HIT association with P70S6K activation following ischaemic stroke Based on our immunoblots, P70S6K activation was altered by ischaemic stroke as indexed by phosphorylated P70S6K to P70S6K proportion (Figures 4 and 5). It is worth noting, as shown in Figures 4B and 5B, that HIT plus I/R increased the

Figure 1. Neurological evaluation in CET and HIT-treated groups compared with sham and ischaemia 24 hours after induction of ischaemia. (n = 8). Data were presented as Mean±SEM. ***p < 0.001, ver. sham group, ###p < 0.001, ###p < 0.01 ver. I/R group. I/R: Ischaemia/reperfusion, CET: continuous endurance training, HIT: high-intensity interval training.

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densitometry of phosphorylated P70S6K compared with the CET group in both the cortical and hippocampal regions (p < 0.05).

Discussion In the present study, we found that pre-ischaemic physical exercises (HIT and CET) significantly increased the neurological scores, locomotion and anxiolytic behaviour in the MCAO model. Both HIT or CET could amplify behavioral parameters solely. Also, there was no statistically significant difference between HIT and CET in behavioural tests. We observed that HIT increased the hippocampal and cortical levels of phosphorylated P70S6K in comparison to CET. Increasing evidence suggests that physical exercise before or after cerebral ischaemia has advantageous therapeutic effect. Mood and psychotic and locomotive disorders are known manifestations of cerebral ischaemic stroke, and physical exercise training is a positive and safe non-pharmacological intervention in ischaemic patients. Therefore, many researchers have focused on the therapeutic effects of physical exercise against toxic effects of focal cerebral ischaemia in patients and animal models. Recently, several categories and intensities of physical aerobic exercise training have been suggested to improve the cerebral ischaemia syndrome. The role of moderate CET in life expectancy and clinical effects in cerebral ischaemia is well accepted. Besides, the HIT model has been proposed as a novel and effective strategy, recently; because it has resulted in more increases in exercise capacity than those accomplished with moderate continuous training [28,29]. Relevant clinical studies have mainly focused on the role of exercise training in ischaemic patients [30,31] and they have demonstrated that such treatment could improve many psychological behaviours such as executive function, memory, social behavior and orientation [32,33]. There is a relationship between ischaemia-induced neuronal damage and behavioural alteration following focal cerebral ischaemia [34]. Anxious behaviour and disability in movement are two major signs observed after cerebral ischaemia in patients. We used neurological score evaluation, open field test and EPM to measure the role of HIT and CET 24 hours after MCAO. Sensory-motor evaluation score was enhanced in both exercised groups after ischaemia. It has been shown that neurological injury was significantly increased 22 hours after MCAO [35] and pre-ischaemic treadmill physical exercise recovered neurological deficit scores [36,37]. Our data are in agreement with these reports [36,37] and show that both HIT and CET ameliorate neurological deficits. Open field test is commonly used for the measurement of anxiety-like behaviour and locomotion. Increased time spent in the centre zone contributes to anxiolytic behaviour and locomotion enhancement [38,39]. It is common to synthesize results of open field test with open arm time and open arm entries in the EPM in the measurement, as both indicate the proclivity of rats to explore anxiogenic locations [40]. Clinical studies are in confirmation that physical exercise had therapeutic effects against psychological abnormalities subsequent to heart failure and cerebral ischaemia [30,41,42], but there is no experimental study on the preventive role of exercise against cerebral

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Figure 2. Open field test in CET and HIT-treated groups compared with sham and ischaemia 24 hours after induction of ischaemia (n = 8). (A) The total distance moved (meters). (B) Total time of centre occupancy (s). Data were presented as mean ± SEM. ***p < 0.001, **p < 0.01, *p < 0.05 ver. sham group, ###p < 0.01 ver. I/R group. I/R, Ischaemia/reperfusion; CET, continuous endurance training; HIT, high-intensity interval training.

ischaemia. However, the protective aerobic exercise training protocol against focal cerebral ischemia is not well recognized. Herein, we assessed that both moderate continuous and highintensity training exercises had identical consequences on anxiety and locomotive behaviour improvement. Results show that enhancement in sensory-motor deficits increased locomotion in exercised rats following cerebral ischaemia. HIT and CET without induction of ischaemia ameliorated the anxious behaviour and increased distance moving compared with the sham group, which indicates that exercise attenuated anxiety-like behaviour in normal rats. Perhaps, this anxiolytic behaviour as a result of training might have weakened the anxious effect after ischaemia. The current study is the first to observe the preventive effects of continuous and high-intensity training on the MCAO experimental model and to find that both types of exercises before induction of ischaemia might recover behavioural deficits such as neurological injury, locomotion and anxiety-like behaviour. In the molecular section, to compare which type of HIT and CET plays a more efficient role against ischaemia, we evaluated the hippocampal and cortical levels of P70S6K in the two pre-ischaemic HIT and CET groups. The

phosphorylated P70S6K level was increased in the HIT group in both the hippocampus and cortex. P70S6K is a major downstream protein in the mTOR pathway and phosphorylation of P70S6K is an important step in the initiation of protein translation and cell survival. Liao and colleagues found that exercise increased P70S6K levels in ischaemic cardiac cells and showed that increased levels of the mTOR pathway induced P70S6K phosphorylation [43]. In contrast, it has been revealed that moderate-intensity training had a more beneficial effect on P70S6K levels compared with high-intensity training in the cardiac cells [43]. Some other investigations have indicated that P70S6K expression was elevated in the muscle cells [44–46]. Additionally, a clinical research has shown that the level of Brain-Derived Neurotrophic Factor (BDNF) was increased in the serum during exercise in ischaemic patients and this BDNF activation might improve memory deficits, anxiety and stress [32]. Our previous in vivo study confirmed that BDNF could be one of the major upstream proteins for activation of P70S6K after cerebral ischaemia in rats [47]. Many lines of evidence have declared that HIT may play a more effective role than other types of training in the

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Figure 3. Elevated plus maze test in CET and HIT-treated groups compared with sham and ischaemia 24 hours after induction of ischaemia (n = 8). (A) Percentage of open arm time. (B) Percentage of open arm entries. Data were presented as mean ± SEM. ***p < 0.001, **p < 0.01, *p < 0.05 ver. sham group, ###p < 0.01 ver. I/R group. I/R, Ischaemia/reperfusion; CET, continuous endurance training; HIT, high-intensity interval training.

improvement of protective signaling pathways in neuronal ischaemic injury [48,49]. Our data claimed that HIT played an effective role on P70S6K expression compared to CET. Increasing data show anxiety attenuates the P70S6K neuronal level and abolishes brain homeostasis [50,51]. Dutheil and coworkers suggested that enhancement of cortisone reduced P70S6K levels and subsequently increased anxiety-like behaviour [50]. However, a protective role of P70S6K against memory impairment in neurological disorders such as cerebral ischaemia, ageing and Alzheimer’s disease have been reported [52–54]; our data showed that P70S6K has a defensive role against anxiety and locomotion. It was established that molecular modifications increased earlier than behavioural alterations [55]. Alteration of P70S6K in the brain 16–24 hours after ischaemia-reperfusion was well accepted [56,57]; therefore we can conclude that HIT could enhance P70S6K levels in the brain and subsequently elevated anxiolytic behaviour and neurological scores. However, timedependent studies should be performed in the future to evaluate the downstream kinases, and so understanding cellular

signaling mechanism during exercise might open new approach against cerebral ischemia. Moreover, long term study probably illustrate the differences between CET and HIT in behavioral tests. The protective role of estradiol on mTOR/P70S6K pathway in focal cerebral ischaemia was documented [58] and in a future study we plan to use normal and ovariectomied female rats in such ischaemic contexts for assessing the role of different genders in exercise and cerebral ischaemia.

Conclusions To summarize, our study first demonstrated the advantageous effect of both aerobic HIT and CET on anxiety, locomotion and neuronal P70S6K levels in the MCAO ischaemic model. HIT and CET had the same effect on behavioural tests in ischaemic animals. On the other hand, the level of cortical and hippocampal phosphorylated P70S6K increased in the HIT group, indicating the priority of molecular modification in comparison to behavioural

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Declaration of interest The authors declare that there are no conflicts of interest. This research was supported by a research fund from faculty of Sport Science, University of Shahid Beheshti. We are also grateful to Neurobiology Research Center of Shahid Beheshti University of Medical Sciences for providing facilities.

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References

Figure 4. The hippocampal protein level of phosphorylated and total P70S6K in sham, CET and HIT-treated groups compared with sham and ischaemia 24 hours after induction of ischaemia by Western blotting (n = 6). (A) Representative Western blots and (B) analysis histogram. Data were presented as mean ± SEM. *p < 0.05 ver. CET+I/R group. I/R, Ischaemia/reperfusion; CET, continuous endurance training; HIT, high-intensity interval training.

Figure 5. The cortical protein level of phosphorylated and total P70S6K in sham, CET and HIT-treated groups compared with sham and ischaemia 24 hours after induction of ischaemia by Western blotting (n = 6). (A) Representative Western blots and (B) analysis histogram. Data were presented as mean ± SEM. *p < 0.05 ver. CET+I/R group. I/R, Ischaemia/reperfusion; CET, continuous endurance training; HIT, high-intensity interval training.

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Differential impact of treadmill training on stroke-induced neurological disorders.

Physical exercise contributes to improving stability against nerve injury caused by ischaemic stroke. Here we aimed to preliminarily investigate the e...
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