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Neuroprotection of Early Locomotor Exercise Poststroke: Evidence From Animal Studies

Published online by Cambridge University Press:  04 June 2015

Pengyue Zhang ,
Jia Xianglei ,
Yang Hongbo ,
Jichuan Zhang  and
Ce Xu
Pengyue Zhang
Affiliation:
Medical Faculty, Kunming University of Science and Technology, Kunming, China Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai, China
Jia Xianglei
Affiliation:
Medical Faculty, Kunming University of Science and Technology, Kunming, China
Yang Hongbo
Affiliation:
Medical Faculty, Kunming University of Science and Technology, Kunming, China
Jichuan Zhang*
Affiliation:
Medical Faculty, Kunming University of Science and Technology, Kunming, China
Ce Xu*
Affiliation:
Medical Faculty, Kunming University of Science and Technology, Kunming, China
*
Correspondence to: Jichuan Zhang or Ce Xu, Medical Faculty, Kunming University of Science and Technology, Yunnan, Kunming, 650500, China. Email: [email protected], [email protected]
Correspondence to: Jichuan Zhang or Ce Xu, Medical Faculty, Kunming University of Science and Technology, Yunnan, Kunming, 650500, China. Email: [email protected], [email protected]
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Abstract

Early locomotor exercise after stroke has attracted a great deal of attention in clinical and animal research in recent years. A series of animal studies showed that early locomotor exercise poststroke could protect against ischemic brain injury and improve functional outcomes through the promotion of angiogenesis, inhibition of acute inflammatory response and neuron apoptosis, and protection of the blood-brain barrier. However, to date, the clinical application of early locomotor exercise poststroke was limited because some clinicians have little confidence in its effectiveness. Here we review the current progress of early locomotor exercise poststroke in animal models. We hope that a comprehensive awareness of the early locomotor exercise poststroke may help to implement early locomotor exercise more appropriately in treatment for ischemic stroke.

Résumé

Neuroprotection conférée par l’exercice locomoteur précoce après un accident vasculaire cérébral : données tirées des études chez l’animal. L’exercice locomoteur précoce après un accident vasculaire cérébral (AVC) a retenu l’attention en recherche clinique et en recherche chez l’animal au cours des dernières années. Plusieurs études chez l’animal ont montré que l’exercice locomoteur précoce après un AVC protégerait contre une lésion ischémique du cerveau et pourrait améliorer l’issue fonctionnelle en favorisant l’angiogenèse, l’inhibition de la réponse inflammatoire aiguë et l’apoptose neuronale ainsi que la protection de la barrière hémato-encéphalique. Cependant, à ce jour, le recours en clinique à l’exercice locomoteur précoce après un AVC a été limité parce que certains cliniciens ont peu confiance en son efficacité. Nous revoyons les progrès actuels dans le domaine de l’exercice locomoteur précoce après un AVC chez des modèles animaux. Nous espérons qu’une sensibilisation à l’exercice locomoteur précoce après un AVC pourra favoriser une utilisation de l’exercice locomoteur précoce de façon plus appropriée dans le traitement de l’AVC ischémique.

Keywords

Cerebral ischemiaEarly exerciseMechanism of neuroprotectionNeuron apoptosis
Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 42 , Issue 4 , July 2015 , pp. 213 - 220
Copyright
Copyright © The Canadian Journal of Neurological Sciences Inc. 2015 

Introduction

Cerebral ischemia is one of the most serious neurological disorders and is the most common cause of permanent disability all over the world.Reference Knecht, Hesse and Oster 1 Its sequelae not only reduce the quality of survivor’s life, but also put a heavy burden on families and society. 2 Although a great deal of effort have been made in past decades, today we still lack effective strategies that can improve functional outcome in stroke survivors.Reference Pérez de la Ossa and Dávalos 3

The early phase postischemia is the critical time window for the functional recovery in which plenty of neuroprotective mechanisms were initiated, such as neurogenesis, functional plasticity, axonal sprouting and synaptogenesis, and attenuation of muscle atrophy in unaffected sides.Reference Jorgensen, Nakayama and Raaschou 4 - Reference Choe, An and Lee 6 This time window is sensitive to specific treatments that can trigger and promote neuroprotective mechanisms in spontaneous recovery.

In recent years, increasing clinic evidence has suggested that early locomotor exercise after stroke facilitated the functional recovery from stroke and had attracted a great deal of attention.Reference Bernhardt, Dewey, Thrift, Collier and Donnan 7 The benefits of early locomotor exercise after stroke included fewer deaths, fewer and less severe complications, less disability, and better quality of life.Reference Dragert and Zehr 8 - Reference Stoller, de Bruin and Knols 10 Moreover, early locomotor exercise poststroke has currently been recommended in a range of clinical guidelines, such as the Clinical Guidelines for Stroke Management 2010 document sponsored by the National Stroke Foundation in Australia. 11 Although early locomotor exercise poststroke was considered an important and potential treatment strategy for stroke, its clinical application is limited. Some clinicians have little confidence in its effectiveness because of the absence of high-quality randomized, double-blind, control clinical trials and an undefined molecular mechanism.Reference McCluskey, Vratsistas-Curto and Schurr 12 , Reference Stinear, Ackerley and Byblow 13

Although there are some differences between patient and animal models, the animal studies can help us explore underlying molecular mechanisms that is difficult to achieve in clinical trials. The unmasked mechanism may increase the willingness of clinicians to implement the early locomotor exercise poststroke in clinical settings. Here we review the mechanism of early locomotor exercise poststroke in animal stroke models in recent years. We hope that a comprehensive awareness of early locomotor exercise may help implement early locomotor exercise more appropriately in treatment for cerebral ischemic stroke.

Search Methodology and Results

We aimed to identify all rodent animal studies relating to cerebral ischemia, early locomotor exercise poststroke, behavioral recovery, and mechanism. We searched PubMed including all years up to January 2015 (English language only). We included animal studies that used global or focal ischemic stroke. Any intervention using early locomotor exercise, such as forced or voluntary locomotor exercise, was included.

Based on the keywords “cerebral ischemia” and “exercise,” we obtained 826 titles. Of these, 258 studies were animal models and their abstracts were identified for further review. Reference lists in these articles were hand-searched for further studies with potential relevance. Finally, 49 studies met the criteria (rodent model, cerebral ischemia, early-initiated [24-72 hours poststroke], and locomotor exercise intervention) and measured the effects of early locomotor exercise postcerebral ischemia on brain repair and so were included in this review (Table 1).

Table 1 References of early exercise after stroke

NGF, nerve growth factors.

Definition of Early Locomotor Exercise

To implement early locomotor exercise appropriately, it is crucial to define the time window of the early phase after stroke. However, there is not a standard definition of early phase either in clinical applications or animal studies. In the clinical setting, 24 hours, the first 3 days, and the first week after stroke onset were considered as early phase.Reference Ada, Dean and Morris 14 , Reference Ada, Dean and Morris 15 The time window is one of the direct guides for clinical therapy. However, the optimal time point for early exercise depends on multiple factors including race, sex, age, lifestyle, complications, and individual differences. Thus the early phase after stroke cannot be defined only by time point in the clinical setting.

This issue becomes simple in animal model because we can control almost all conditions in experiments including the type of animal, sex, age, and severity of stroke. The middle cerebral artery occlusion is widely used in rodent stroke model. In most reports, early exercise was initiated during 24 to 72 hours after middle cerebral artery occlusion in rodents with 60 to 120 minutes of ischemiaReference Zhang, Zhang and Zhang 16 - Reference Lee, Kim and Park 20 (Table 1). Thus the exercise begun 24 to 72 hours after stroke was defined as early exercise in this review, with the training period lasting from 1 to 4 weeks.

The locomotor exercise program in this review included voluntary exercise and forced exercise (constant intensity during all training periods and gradually increased intensity during the first few days) (Table 1).

Histological and Functional Improvement

The death of neurons is the disastrous consequence of cerebral ischemia, which leads to serious histological damages and the formation of an infarct zone in brain parenchyma. The neurons in the ischemic core die via irreversible necrosis and apoptosis. Subsequently, most cells in the penumbra, region that surrounds the infarct zone, undergo apoptosis gradually after stroke.Reference Broughton, Reutens and Sobey 21 These cells can potentially be rescued in the early phase of cerebral ischemia by inhibiting the apoptotic pathway or by recovering the cerebral blood. Because decreased neuron death means reduced infarct volume and promoted functional recovery, the treatment strategies to date that could reduce infarct volume are potential protocols in stroke treatment.

Locomotor exercise at early phase is one kind of treatment in after-stroke recovery. However, early locomotor exercise did not reduce infarct volume consequentially; the infarct volume in ischemic rats may even be enlarged by conditioned overuse of the affected limb and high-intensity exercise at early phase after stroke.Reference Humm, Kozlowski and James 22 - Reference Bland, Pillai and Aronowski 24 Early locomotor exercise with a proper intensity reduced the infarct volume.Reference Yang, Wang, Wang and Yu 25 Although early locomotor exercise significantly promoted motor coordination and alleviated neurological deficits,Reference Yang, Wang, Wang and Yu 25 , Reference Shimada, Hamakawa and Ishida 26 the promoted functional recovery is not accompanied by reduced infarct volume.Reference Marin, Williams and Hale 27 Furthermore, the effect of early locomotor exercise on recovery is timing window–dependent. YangReference Yang, Wang and Wang 28 and Rasmus et alReference Nielsen, Samson, Simonsen and Jensen 29 demonstrated that rats with one week of mild treadmill training initiated 24 hours after operation had reduced infarct volume and better functional recovery than rats with equal training initiated one week after operation. Our group also demonstrated that early treadmill training with gradually increased intensity significantly reduced infarct volume and promoted functional recovery of motor and memory. Moreover, aging is often accompanied by stroke attack. Two weeks of early locomotor exercise decreased the infarct volume both in young and old rats compared with the control group, but the young rats had a smaller infarct volume than did the older rats.Reference Wang, Yu and Yang 30

In summary, these experimental studies indicate that locomotor exercise with mild to moderate intensity initiated early may decrease histological damage and enhance functional recovery from cerebral ischemia.

Neuroprotective Mechanism of Early Exercise

Early locomotor exercise initiates multiple neuroprotective responses in injured brains such as change of cerebral blood flow, gene expression, angiogenesis, neurogenesis, mitochondrial biogenesis, suppression of apoptosis, and neuroinflammation response. Their synergistic effect contributes to neuroprotection and subsequent functional recovery (Table 1).

Early Locomotor Exercise Attenuates Neuroinflammation Response

Cerebral ischemia is accompanied with the inflammatory responses, such as the production of proinflammatory cytokines, chemokines, and adhesion molecules and activation of the resident glial cells. These processes start within hours after ischemia and persist for months.Reference Barone and Feuerstein 31 , Reference Wang, Tang and Yenari 32 Although inflammatory responses exerted some beneficial effects in recovery from stroke,Reference Lucas, Rothwell and Gibson 33 - Reference Stoll and Jander 35 accumulating evidence showed that inflammatory response in the acute ischemic period was one of the main factors that led to brain damage and exacerbated ischemic injury in potentially viable tissues through secretion of deleterious molecules, such as glutamate, and production of reactive oxygen species and nitric oxide.Reference Dheen, Kaur and Ling 36 - Reference Eltzschig and Eckle 40 Some experimental evidence have demonstrated that inhibition of acute inflammatory responses with antagonists, neutralizing antibodies, or gene knockouts relieved the detrimental effects and markedly improved functional recovery.Reference Iadecola, Zhang and Casey 41 , Reference Hewlett and Corbett 42

Existing evidence shows that physical exercise diminishes inflammation in some chronic diseases and in aged mice.Reference Beavers, Brinkley and Nicklas 43 The molecular mechanism involves the reduction of macrophage infiltration, expression of inducible nitric oxide synthase and tumor necrosis factor-alpha in the heart and expression of chemokines and cytokines in the circulatory system.Reference Botta, Laher and Beam 44 - Reference Gomes, Simoes and Mortara 46 Interestingly, a recent article has indicated that preischemic physical exercise led to chronically increased expression of tumor necrosis factor-alpha during exercise, which conversely ameliorated inflammatory injury induced by ischemia/reperfusion.Reference Ding, Young and Luan 47 A possible explanation is that the chronically proinflammatory response during exercise led to ischemic tolerance, a phenomenon in which minor injury before ischemia led to a greater tolerance to subsequent serious injury. Recent research has focused on the effect of postischemic physical exercise on the acute inflammatory response. Our data indicated that early locomotor exercise after stroke significantly attenuated the acute neuroinflammation through decreasing proinflammatory cytokines and cell adhesion molecules, suppressing the activation of astrocytosis and microglia, and attenuating the detriment of over-released glutamate.Reference Zhang, Zhang and Pu 19 , Reference Zhang, Bai and Hu 48 Furthermore, we found that early locomotor exercise protects blood-brain barrier (BBB) integrity against ischemia/refusion injury.Reference Zhang, Zhang and Shen 49 The disrupted BBB is a critical early event that initiates the inflammatory cascade and exaggerates edema, which ultimately results in poor outcomes.Reference Spatz 50 Recent studies have indicated Toll-like receptor (TLR) signaling pathways are also involved the neuroprotective action of early locomotor exercise. TLRs are a group of important receptors in the brain’s innate immune system; they play a critical role in initiating and modulating the inflammatory cascade caused by cerebral ischemia through recruiting and linking to their endogenous ligands released from damaged neuronal cells.Reference Kaczorowski, Mollen and Edmonds 51 - Reference Winters, Winters and Gorup 53 Studies have shown that early locomotor exercise decreased TLR expression on cell-surface and inflammatory cytokine production in monocytes in ischemic brain tissue.Reference Gleeson, Mcfarlin and Flynn 54 - Reference Zwagerman, Plumlee and Guthikonda 56 The main downstream targets of TLR2/4, MyD88, and nuclear factor-κB were also reduced by early exercise following cerebral ischemia.Reference Ma, He and Qiang 57 In summary, early locomotor exercise after stroke may attenuate acute inflammatory responses via reduced expression of proinflammatory cytokines and inhibited BBB dysfunction so as to confer neuroprotective action.

Early Locomotor Exercise Suppresses Neural Apoptosis in Penumbra

Cerebral ischemia leads to irreversible death of neurons in the ischemic core. However, some neurons in penumbra survive with dysfunction and then undergo apoptosis if they do not receive effective therapeutic treatment.Reference Ribe, Serrano-Saiz and Akpan 58 - Reference Broughton, Reutens and Sobey 60 Thus, these injured neurons could be rescued in early-phase postischemia, and suppression of apoptosis may potentially be an opportunity to salvage these neurons and then alleviate brain injury.Reference Martinou, Dubois-Dauphin and Staple 61 , Reference Zhao, Yenari and Cheng 62 Increasing evidence shows that appropriate locomotor exercise could suppress apoptosis in many diseases,Reference Haack, Luu and Cho 63 , Reference Kavazis, Smuder and Min 64 particularly in ischemic myocardial infarctionReference Quindry, French and Hamilton 65 , Reference Kavazis, Mcclung and Hood 66 and Alzheimer diseaseReference Um, Kang and Leem 67 by reducing the expression of proapoptotic proteins and increasing the expression of antiapoptotic proteins.Reference French, Hamilton and Quindry 68 - Reference Kwak, Song and Lawler 70 Two-week early locomotor exercise started at 48 or 72 hours poststroke significantly reduces the number of TdT-mediated dUTP-biotin nick-end labeling–positive cells and suppressed autophagosomes.Reference Zhang, Hu and Luo 71 - Reference Lee, Kim and Kim 73 Even early locomotor exercise started at 24 hours after stroke also significantly improves neurological function by decreasing caspase-3 and cleaved caspase-3 expression and the number of apoptotic cells detected by Fluoro-Jade-B staining and TdT-mediated dUTP-biotin nick-end labeling concurrently by increasing Bcl-2 (a key antiapoptotic protein) expression detected by western blotting.Reference Zhang, Zhang and Zhang 16 , Reference Sim, Kim and Kim 74 , Reference Sim, Kim, Kim, Shin and Kim 75 These results indicate that suppressing neural apoptosis in the penumbra may be the potential underlying mechanism conferred to the neuroprotective mechanism induced by early locomotor exercise following cerebral ischemia.

Early Locomotor Exercise Increases Expression of Neurotrophic Factors

Neurotrophic factors play crucial roles in neuronal survival, repair, and recovery from stroke.Reference Ang and Gomez-Pinilla 76 However, their clinical application is limited because the recombinant neurotrophic factors cannot cross the BBB.Reference Poduslo and Curran 77 It is well-known that exercise can upregulate the expression of nerve growth factors in rats with both normal and diseased brains, such as brain-derived neurotrophic factor (BDNF),Reference Quirie, Hervieu and Garnier 78 - Reference Sartori, Vieira and Ferrari 81 nerve growth factors, and neurotrophin, and so on.

Similarly, recent reports indicate that early locomotor exercise following stroke increases the expression of neurotrophic factors, such as BDNF and insulin-like growth factor (IGF), the possible mechanisms involved in the 5-HT, Trk, and AKT signaling pathways.Reference Liu, Huang and Lin 82 - Reference Sun, Ke, Yip, Hu, Zheng and Tong 87 The increased BDNF induced by early locomotor exercise is mainly distributed in the contralateral hemisphere and the penumbra in the ipsilateral hemisphere.Reference Kim, Bang and Han 88 The expression levels of nerve growth factors and Midkine are significantly upregulated in the cells around the infarct zone of the ischemic rats that received low-intensity early locomotor exercise compared with the ischemia-only sedentary rats.Reference Matsuda, Sakakima and Yoshida 17 Early locomotor exercise increases neurotrophin-4 protein level in the bilateral hemispheres compared with the ischemia-only sedentary rats, particularly in the contralateral hemisphere and the zone that adjacent to the ischemic region; this increase was detected as early as day 9 after ischemia.Reference Chung, Kim and Bang 89 The study by Chang et al found that early locomotor exercise increases the IGF-I concentration through promoted IGF-I entrance into the affected brain zone and increased its expression. Inhibiting IGF-I signaling eliminates such protective effects.Reference Chang, Yang and Wang 90 A study conducted by Ohwatashi et al found that early locomotor exercise induces increased expression of glial cell line-derived neurotrophic factor in rats who underwent photochemical infarction.Reference Ohwatashi, Ikeda and Harada 91 It is noteworthy that Liu et alReference Liu, Huang and Lin 82 demonstrated that early locomotor exercise started at 24 hours significantly increased the expression of netrin-1 and its receptors, which regulate diverse recovery processes including neuron survival and migration,Reference Llambi, Causeret and Bloch-Gallego 92 , Reference Tang, Jang and Okada 93 axonal outgrowth and branching,Reference Dent, Barnes and Tang 94 and angiogenesis.Reference Wilson, Ii and Park 95

Early Locomotor Exercise Enhances the Angiogenesis and Improves Cerebral Blood Flow in the Ischemic Zone

Angiogenesis is a neuroprotective response induced by hypoxia within a few hours after the onset of stroke. The expression of a group of angiogenic factors including vascular endothelial growth factor, Ang1/2, and their receptor Tie2 in infarct hemisphere was gradually upregulated for weeks after stroke. These proteins trigger the proliferation of endothelial cells and neovascularization.Reference Sun, Jin and Xie 96 - Reference Beck, Acker and Wiessner 99 Krupinski et al found some vascular buds and connections in an ischemic rat by brain vascular cast method.Reference Krupinski, Stroemer and Slevin 100 Newly formatted blood vessels not only improve the exchange of oxygen and glucose through increased blood flow,Reference Jiang, Zhang and Ding 101 , Reference Hayashi, Deguchi and Nagotani 102 but also remove damaged tissues and ameliorate the microenvironment in hypoxic tissue.Reference Manoonkitiwongsa, Jackson-Friedman and Mcmillan 103 The improved microenvironment rescues the injured neurons and promotes the proliferation and migration of neural stem cells.Reference Petraglia, Marky and Walker 104 , Reference Li, Ford and Lavik 105 Indeed, clinical observation found that stroke patients with more newly formatted blood vessels survive a longer time.Reference Wei, Erinjeri and Rovainen 106 , Reference Krupinski, Kaluza and Kumar 107 Thus, improving angiogenesis after stroke plays a crucial role in recovery from stroke and is a potential strategy for treatment of ischemia.Reference Arenillas, Sobrino and Castillo 108 , Reference Ergul, Alhusban and Fagan 109

Early locomotor exercise after ischemia has been shown to augment angiogenesis through increasing the messenger RNA transcription and protein translation of angiopoietins, such as vascular endothelial growth factorReference Ma, Qiang and He 110 , PECAM-1Reference Sakakima, Khan and Dhammu 72 , CD31Reference Hu, Zheng and Yan 111 , Ang1, and their receptor Tie2.Reference Zhang, Yu and Zhou 112 , Reference Zheng, Zhu and Bai 113 Endothelial nitric oxide synthesis may be an underlying mechanism because the lack of endothelial nitric oxide synthase abolishes the beneficial effects of early locomotor exercise on angiogenesis.Reference Gertz, Priller and Kronenberg 114 Recently, we demonstrated that these newly formatted vessels increased by early locomotor exercise indeed give rise to new functional vessels and improve the cerebral blood flow in ischemic brain zone visualized by laser speckle flowmetry, a noninvasive imaging blood flow technique.Reference Zhang, Yu and Zhou 112 The similar result was achieved in Yang’s study, which reported increased CD31-positive blood vessel density in the affected striatum.Reference Yang, Chang, Wang and Wang 115 Furthermore, an in vitro study indicated that a modest flow induced by appropriate locomotor exercise decreases brain microvascular endothelial cells apoptosis in the ischemic condition.Reference Tian, Zhang and Tian 116 These results suggested that early locomotor exercise can improve cerebral blood flow through angiogenesis and increase blood flow rate in the ischemic brain zone.

Early Locomotor Exercise Promotes Neuroplasticity: Neurogenesis and Synaptic Reorganization

Neuroplasticity is a critical element in brain repair after stroke. Accumulative evidence has suggested that some newborn neurons after stroke were functionally recruited and formed appropriate synapses with the existing neurons in hippocampus.Reference Liu, Wang and Zhu 117 - Reference Nakatomi, Kuriu and Okabe 119 In addition to neurogenesis, synaptic reorganization is another key constituent in functional recovery following stroke.Reference Font, Arboix and Krupinski 120 The neurons in peri-infarct region of ipsilateral hemisphere and the contralateral hemisphere form some new synapses with survived neurons and newborn neurons.Reference Yiu and He 121

There is increasing evidence to show that locomotor exercise promoted neuroplasticity both in normal and ischemic animals.Reference Ang and Gomez-Pinilla 76 , Reference Rhodes, van Praag and Jeffrey 122 Several reports have shown that locomotor exercise initiated within 7 days after stroke enhances neurogenesis and functional recovery.Reference Luo, Jiang and Zhou 123 Some recent studies have detected the change of protein expression profile induced by early locomotor exercise in the cortex of rats with stroke. These results suggest that early locomotor exercise after stroke upregulate a group of proteins that promote synaptic plasticity, such as growth-associated protein 43 (GAP43, the key axon growth-associated protein), Syn1, synaptosomal-associated protein (SNAP-25), PSD95, and others.Reference Mizutani, Sonoda and Yamada 124 - Reference Mizutani, Sonoda and Hayashi 129 Accordingly, increased neurogenesis was detected in the hippocampus dentate gyrus and peri-infarct regions in rats who underwent early locomotor exercise.Reference Zheng, Zhang and Luo 130 During spontaneous recovery after ischemia, many of these newborn neurons undergo apoptosis,Reference Gould, Beylin and Tanapat 131 but early locomotor exercise significantly increases the neurogenesis and decreases the number of apoptotic cells.Reference Zhang, Hu and Luo 71 However, some reports show that early locomotor exercise poststroke reduces neurogenesis in the subventricular zone and dentate gyrus.Reference Komitova, Zhao and Gido 132 - Reference Lee, Kim, Kim and Yoon 134 These inconsistent results could be due to different models and exercise protocols used. Ameliorative neuroplasticity can be detected by electrophysiology. The results from Tang et alReference Tang, Yang and Hu 135 , Reference Tang, Tan and Yang 136 indicate that early locomotor exercise enhanced activity-dependent long-term depression through PICK1-dependent mechanisms and an increased expression level of AMPA receptor subunits that can increase synaptic transmission. Thus early locomotor exercise postischemia promotes neuroplasticity through neurogenesis and synaptogenesis and increases the functional synapse.

Early Locomotor Exercise Promotes Mitochondrial Biogenesis

Mitochondria is a critical organelle that supports the neuronal survival, metabolism, synthesis, and release of neurotransmitters and recovery from injury.Reference Cheng, Hou and Mattson 137 , Reference Garesse and Vallejo 138 However, mitochondrion play opposite roles during cerebral ischemic injury. On the one hand, injured mitochondria releases a great deal of reactive oxygen species that initiate detrimental cascade; on the other hand, biogenesis of functional mitochondria induced by stroke is helpful for neuroprotection and recovery.Reference Cheng, Hou and Mattson 137 , Reference Onyango, Lu and Rodova 139 Thus, the strategy to decrease mitochondria damage and increase mitochondrial biogenesis would be important to neuroprotective treatment after stroke.Reference Valerio, Bertolotti and Delbarba 140 Consistent evidence suggests that exercise increases mitochondrial biogenesis in healthy and ischemic brains.Reference Steiner, Murphy and Mcclellan 141 - Reference Bayod, Del and Canudas 143 Recent evidence from our laboratory shows that early locomotor exercise started 24 hours after stroke increases mitochondrial DNA content and significantly enhances the messenger RNA and protein expression of three transcription factors considered critical for mitochondrial gene transcription and DNA replication: PGC-1, NRF-1, and TFAM.Reference Zhang, Wu and Sha 144 , Reference Zhang, Wu and Zhang 145 These results indicate that early locomotor exercise after stroke could enhance mitochondrial biogenesis and may serve as a key component of early locomotor exercise–induced neuroprotective mechanisms in the ischemic brain.

Summary and Prospects

Locomotor exercise is an effective, inexpensive, home-based, and accessible intervention strategy. Early locomotor exercise poststroke has attracted a great deal of attention in rehabilitative centers and laboratories. Animal studies have increasingly revealed that early locomotor exercise induced neuroprotective mechanisms in the ischemic brain; randomized control trials with larger sample number are further exploring the optimal early locomotor exercise protocol. This evidence from clinical and animal studies indicates that early locomotor exercise poststroke was beneficial for recovery from cerebral ischemia and that it can be applied safely. However, to apply early locomotor exercise in clinical practice and maximize functional outcome, the choice of interventional protocol should be considered carefully. The first consideration is how to choose the type of locomotor exercise. Cumulative evidence indicates that different exercise protocols could lead to an entirely different outcome.Reference Ke, Yip, Li, Zheng and Tong 84 , Reference Ke, Yip, Li, Zheng, Tam and Tong 86 , Reference Yang, Chang, Wang and Wang 115 There are many locomotor exercise manipulations that could be used conveniently, but so far this is no unified standard to assist in choosing the optimum type. The second consideration is whether early locomotor exercise combined with other rehabilitative treatments or drugs is more reasonable than locomotor exercise only.Reference Wang, Feng, Du, Wang and Zhang 146 , Reference Gherardini, Gennaro and Pizzorusso 147 A related rehabilitative treatment may be functional electrical stimulation, acupuncture, music stimulus, light stimulus, skilled training, and so on. Drugs can include multiple agents that alleviate inflammatory response and neuronal apoptosis and promote angiogenesis and neurogenesis. Additionally, some locomotor exercise can be carried out under the help of body-weight support or a robot.Reference Li, Rong, Ke, Hu and Tong 148 The third consideration is how we can determine the amount and intensity of early locomotor exercise based on different levels of severity in a stroke patient. According to our knowledge from animal studies and clinic observations, low and gradually increased exercise intensity should be performed in the early phase after stroke.Reference Lee, Kim and Park 20 , Reference Shih, Yang and Wang 125 , Reference Austin, Ploughman, Glynn and Corbett 149

In summary, early exercise poststroke was safe, feasible, and effective (Table 1). But its implementation in a clinical setting should be cautiously introduced and based on each individual’s condition.

Acknowledgments and Funding

The present study is supported by the Foundation of Yunnan Educational Committee (KKJA201360028), Natural Science Foundation of Kunming University of Science and Technology (KKSY201360073), and Chinese National Natural Science Foundation (81460351, 81272169, 81201502, 81171856, and 81171855).

Disclosures

The authors have no disclosures.

References

1. Knecht, S, Hesse, S, Oster, P. Rehabilitation after stroke. Dtsch Arztebl Int. 2011;108:600.Google ScholarPubMed
2. The Atlas of Heart Disease and Stroke 2011. Available from:http://www.who.int/cardiovascular_diseases/resources/atlas/en/. Accessed March 29, 2014.Google Scholar
3. Pérez de la Ossa, N, Dávalos, A. Neuroprotection in cerebral infarction: the opportunity of new studies. Cerebrovasc Dis. 2007;24(Suppl 1):153-156.CrossRefGoogle ScholarPubMed
4. Jorgensen, HS, Nakayama, H, Raaschou, HO, et al. Outcome and time course of recovery in stroke. Part II: time course of recovery. The Copenhagen Stroke Study. Arch Phys Med Rehabil. 1995;76:406-412.CrossRefGoogle ScholarPubMed
5. Kreisel, SH, Hennerici, MG, Bazner, H. Pathophysiology of stroke rehabilitation: the natural course of clinical recovery, use-dependent plasticity and rehabilitative outcome. Cerebrovasc Dis. 2007;23:243-255.CrossRefGoogle ScholarPubMed
6. Choe, MA, An, GJ, Lee, YK, et al. Effect of early low-intensity exercise on rat hind-limb muscles following acute ischemic stroke. Biol Res Nurs. 2006;7:163-174.CrossRefGoogle ScholarPubMed
7. Bernhardt, J, Dewey, H, Thrift, A, Collier, J, Donnan, G et al. A very early rehabilitation trial for stroke (avert): phase II safety and feasibility. Stroke. 2008;39:390-396.CrossRefGoogle ScholarPubMed
8 Dragert, K, Zehr, EP. High-intensity unilateral dorsiflexor resistance training results in bilateral neuromuscular plasticity after stroke. Exp Brain Res. 2012;225:93-104.CrossRefGoogle ScholarPubMed
9. Shimodozono, M, Noma, T, Nomoto, Y, et al. Benefits of a repetitive facilitative exercise program for the upper paretic extremity after subacute stroke: a randomized controlled trial. Neurorehabil Neural Repair. 2012;27:296-305.CrossRefGoogle ScholarPubMed
10. Stoller, O, de Bruin, ED, Knols, RH, et al. Effects of cardiovascular exercise early after stroke: systematic review and meta-analysis. BMC Neurol. 2012;12:45.CrossRefGoogle ScholarPubMed
11. Management CGFA Clinical guidelines for acute stroke management. Available from: http://strokefoundation.com.au/health-professionals/tools-and-resources/clinical-guidelines-for-stroke-prevention-and-management/. (Accessed March 29, 2014).Google Scholar
12. McCluskey, A, Vratsistas-Curto, A, Schurr, K. Barriers and enablers to implementing multiple stroke guideline recommendations: a qualitative study. BMC Health Serv Res. 2013;13:323.CrossRefGoogle ScholarPubMed
13. Stinear, C, Ackerley, S, Byblow, W. Rehabilitation is initiated early after stroke, but most motor rehabilitation trials are not: a systematic review. Stroke. 2013;44:2039-2045.CrossRefGoogle Scholar
14. Ada, L, Dean, CM, Morris, ME. Supported treadmill training to establish walking in non-ambulatory patients early after stroke. BMC Neurol. 2007;7:29.CrossRefGoogle ScholarPubMed
15. Ada, L, Dean, CM, Morris, ME, et al. Randomized trial of treadmill walking with body weight support to establish walking in subacute stroke: the MOBILISE trial. Stroke. 2010;41:1237-1242.CrossRefGoogle ScholarPubMed
16. Zhang, P, Zhang, Y, Zhang, J, et al. Early exercise protects against cerebral ischemic injury through inhibiting neuron apoptosis in cortex in rats. Int J Mol Sci. 2013;14:6074-6089.CrossRefGoogle ScholarPubMed
17. Matsuda, F, Sakakima, H, Yoshida, Y. The effects of early exercise on brain damage and recovery after focal cerebral infarction in rats. Acta Physiol (Oxf). 2011;201:275-287.Google ScholarPubMed
18. Seo, HG, Kim, DY, Park, HW, et al. Early motor balance and coordination training increased synaptophysin in subcortical regions of the ischemic rat brain. J Korean Med Sci. 2010;25:1638-1645.CrossRefGoogle ScholarPubMed
19. Zhang, P, Zhang, Q, Pu, H, et al. Very early-initiated physical rehabilitation protects against ischemic brain injury. Front Biosci (Elite Ed). 2012;4:2476-2489.Google ScholarPubMed
20. Lee, SU, Kim, DY, Park, SH, et al. Mild to moderate early exercise promotes recovery from cerebral ischemia in rats. Can J Neurol Sci. 2009;36:443-449.CrossRefGoogle ScholarPubMed
21. Broughton, BR, Reutens, DC, Sobey, CG. Apoptotic mechanisms after cerebral ischemia. Stroke. 2009;40:e331-e339.CrossRefGoogle ScholarPubMed
22. Humm, JL, Kozlowski, DA, James, DC, et al. Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period. Brain Res. 1998;783:286-292.CrossRefGoogle ScholarPubMed
23. Kozlowski, DA, James, DC, Schallert, T. Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci. 1996;16:4776-4786.CrossRefGoogle ScholarPubMed
24. Bland, ST, Pillai, RN, Aronowski, J, et al. Early overuse and disuse of the affected forelimb after moderately severe intraluminal suture occlusion of the middle cerebral artery in rats. Behav Brain Res. 2001;126:33-41.Google ScholarPubMed
25. Yang, YR, Wang, RY, Wang, PS, Yu, SM. Treadmill training effects on neurological outcome after middle cerebral artery occlusion in rat. Can J Neurol Sci. 2003;30:252-258.CrossRefGoogle Scholar
26. Shimada, H, Hamakawa, M, Ishida, A, et al. Low-speed treadmill running exercise improves memory function after transient middle cerebral artery occlusion in rats. Behav Brain Res. 2012;243C:21-27.Google Scholar
27. Marin, R, Williams, A, Hale, S, et al. The effect of voluntary exercise exposure on histological and neurobehavioral outcomes after ischemic brain injury in the rat. Physiol Behav. 2003;80:167-175.Google ScholarPubMed
28. Yang, YR, Wang, RY, Wang, PS. Early and late treadmill training after focal brain ischemia in rats. Neurosci Lett. 2003;339:91-94.CrossRefGoogle ScholarPubMed
29. Nielsen, RK, Samson, KL, Simonsen, D, Jensen, W. Effect of early and late rehabilitation onset in a chronic rat model of ischemic stroke- assessment of motor cortex signaling and gait functionality over time. IEEE Trans Neural Syst Rehabil Eng. 2013;21:1006-1015.CrossRefGoogle Scholar
30. Wang, RY, Yu, SM, Yang, YR. Treadmill training effects in different age groups following middle cerebral artery occlusion in rats. Gerontology. 2005;51:161-165.CrossRefGoogle ScholarPubMed
31. Barone, FC, Feuerstein, GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab. 1999;19:819-834.CrossRefGoogle ScholarPubMed
32. Wang, Q, Tang, XN, Yenari, MA. The inflammatory response in stroke. J Neuroimmunol. 2007;184:53-68.CrossRefGoogle ScholarPubMed
33. Lucas, SM, Rothwell, NJ, Gibson, RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006;147(Suppl 1):S232-S240.CrossRefGoogle Scholar
34. Nakajima, K, Yamamoto, S, Kohsaka, S, et al. Neuronal stimulation leading to upregulation of glutamate transporter-1 (GLT-1) in rat microglia in vitro. Neurosci Lett. 2008;436:331-334.CrossRefGoogle ScholarPubMed
35. Stoll, G, Jander, S. The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol. 1999;58:233-247.CrossRefGoogle ScholarPubMed
36. Dheen, ST, Kaur, C, Ling, EA. Microglial activation and its implications in the brain diseases. Curr Med Chem. 2007;14:1189-1197.CrossRefGoogle ScholarPubMed
37. Barger, SW, Goodwin, ME, Porter, MM, et al. Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation. J Neurochem. 2007;101:1205-1213.CrossRefGoogle ScholarPubMed
38. Gibson, CL, Coughlan, TC, Murphy, SP. Glial nitric oxide and ischemia. Glia. 2005;50:417-426.CrossRefGoogle ScholarPubMed
39. Offner, H, Subramanian, S, Parker, SM, et al. Experimental stroke induces massive, rapid activation of the peripheral immune system. J Cereb Blood Flow Metab. 2006;26:654-665.CrossRefGoogle ScholarPubMed
40. Eltzschig, HK, Eckle, T. Ischemia and reperfusion—from mechanism to translation. Nat Med. 2011;17:1391-1401.CrossRefGoogle ScholarPubMed
41. Iadecola, C, Zhang, F, Casey, R, et al. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci. 1997;17:9157-9164.CrossRefGoogle ScholarPubMed
42. Hewlett, KA, Corbett, D. Delayed minocycline treatment reduces long-term functional deficits and histological injury in a rodent model of focal ischemia. Neuroscience. 2006;141:27-33.CrossRefGoogle Scholar
43. Beavers, KM, Brinkley, TE, Nicklas, BJ. Effect of exercise training on chronic inflammation. Clin Chim Acta. 2010;411:785-793.CrossRefGoogle ScholarPubMed
44. Botta, A, Laher, I, Beam, J, et al. Short term exercise induces PGC-1alpha, ameliorates inflammation and increases mitochondrial membrane proteins but fails to increase respiratory enzymes in aging diabetic hearts. PLoS One. 2013;8:e70248.CrossRefGoogle ScholarPubMed
45. You, T, Arsenis, NC, Disanzo, BL, et al. Effects of exercise training on chronic inflammation in obesity: current evidence and potential mechanisms. Sports Med. 2013;43:243-256.CrossRefGoogle ScholarPubMed
46. Gomes, DSS, Simoes, PS, Mortara, RA, et al. Exercise-induced hippocampal anti-inflammatory response in aged rats. J Neuroinflammation. 2013;10:61.Google Scholar
47. Ding, YH, Young, CN, Luan, X, et al. Exercise preconditioning ameliorates inflammatory injury in ischemic rats during reperfusion. Acta Neuropathol. 2005;109:237-246.CrossRefGoogle ScholarPubMed
48. Zhang, A, Bai, Y, Hu, Y, et al. The effects of exercise intensity on p-NR2B expression in cerebral ischemic rats. Can J Neurol Sci. 2012;39:613-618.CrossRefGoogle ScholarPubMed
49. Zhang, Y, Zhang, P, Shen, X, et al. Early exercise protects the blood-brain barrier from ischemic brain injury via the regulation of MMP-9 and occludin in rats. Int J Mol Sci. 2013;14:11096-11112.CrossRefGoogle ScholarPubMed
50. Spatz, M. Past and recent BBB studies with particular emphasis on changes in ischemic brain edema: dedicated to the memory of Dr. Igor Klatzo. Acta Neurochir Suppl. 2010;106:21-27.CrossRefGoogle Scholar
51. Kaczorowski, DJ, Mollen, KP, Edmonds, R, et al. Early events in the recognition of danger signals after tissue injury. J Leukoc Biol. 2008;83:546-552.CrossRefGoogle ScholarPubMed
52. Wang, Y, Ge, P, Zhu, Y. TLR2 and TLR4 in the brain injury caused by cerebral ischemia and reperfusion. Mediators Inflamm. 2013;2013:124614.Google ScholarPubMed
53. Winters, L, Winters, T, Gorup, D, et al. Expression analysis of genes involved in TLR2-related signaling pathway: inflammation and apoptosis after ischemic brain injury. Neuroscience. 2013;238:87-96.CrossRefGoogle ScholarPubMed
54. Gleeson, M, Mcfarlin, B, Flynn, M. Exercise and Toll-like receptors. Exerc Immunol Rev. 2006;12:34-53.Google ScholarPubMed
55. Flynn, MG, Mcfarlin, BK. Toll-like receptor 4: link to the anti-inflammatory effects of exercise? Exerc Sport Sci Rev. 2006;34:176-181.CrossRefGoogle Scholar
56. Zwagerman, N, Plumlee, C, Guthikonda, M, et al. Toll-like receptor-4 and cytokine cascade in stroke after exercise. Neurol Res. 2010;32:123-126.CrossRefGoogle ScholarPubMed
57. Ma, Y, He, M, Qiang, L. Exercise therapy downregulates the overexpression of TLR4, TLR2, MyD88 and NF-kappaB after cerebral ischemia in rats. Int J Mol Sci. 2013;14:3718-3733.CrossRefGoogle ScholarPubMed
58. Ribe, EM, Serrano-Saiz, E, Akpan, N, et al. Mechanisms of neuronal death in disease: defining the models and the players. Biochem J. 2008;415:165-182.CrossRefGoogle ScholarPubMed
59. Yuan, J. Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis. 2009;14:469-477.CrossRefGoogle ScholarPubMed
60. Broughton, BRS, Reutens, DC, Sobey, CG. Apoptotic mechanisms after cerebral ischemia. Stroke. 2009;40:e331-e339.CrossRefGoogle ScholarPubMed
61. Martinou, JC, Dubois-Dauphin, M, Staple, JK, et al. Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron. 1994;13:1017-1030.CrossRefGoogle ScholarPubMed
62. Zhao, H, Yenari, MA, Cheng, D, et al. Bcl-2 transfection via herpes simplex virus blocks apoptosis-inducing factor translocation after focal ischemia in the rat. J Cereb Blood Flow Metab. 2004;24:681-692.CrossRefGoogle ScholarPubMed
63. Haack, D, Luu, H, Cho, J, et al. Exercise reverses chronic stress-induced Bax oligomer formation in the cerebral cortex. Neurosci Lett. 2008;438:290-294.CrossRefGoogle ScholarPubMed
64. Kavazis, AN, Smuder, AJ, Min, K, et al. Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72. Am J Physiol Heart Circ Physiol. 2010;299:H1515-H1524.CrossRefGoogle ScholarPubMed
65. Quindry, J, French, J, Hamilton, K, et al. Exercise training provides cardioprotection against ischemia-reperfusion induced apoptosis in young and old animals. Exp Gerontol. 2005;40:416-425.CrossRefGoogle ScholarPubMed
66. Kavazis, AN, Mcclung, JM, Hood, DA, et al. Exercise induces a cardiac mitochondrial phenotype that resists apoptotic stimuli. Am J Physiol Heart Circ Physiol. 2008;294:H928-H935.Google ScholarPubMed
67. Um, HS, Kang, EB, Leem, YH, et al. Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer’s disease in an NSE/APPsw-transgenic model. Int J Mol Med. 2008;22:529-539.Google Scholar
68. French, JP, Hamilton, KL, Quindry, JC, et al. Exercise-induced protection against myocardial apoptosis and necrosis: MnSOD, calcium-handling proteins, and calpain. FASEB J. 2008;22:2862-2871.CrossRefGoogle ScholarPubMed
69. Ghosh, S, Khazaei, M, Moien-Afshari, F, et al. Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am J Physiol Renal Physiol. 2009;296:F700-F708.CrossRefGoogle ScholarPubMed
70. Kwak, HB, Song, W, Lawler, JM. Exercise training attenuates age-induced elevation in Bax/Bcl-2 ratio, apoptosis, and remodeling in the rat heart. FASEB J. 2006;20:791-793.CrossRefGoogle ScholarPubMed
71. Zhang, L, Hu, X, Luo, J, et al. Physical exercise improves functional recovery through mitigation of autophagy, attenuation of apoptosis and enhancement of neurogenesis after MCAO in rats. BMC Neurosci. 2013;14:46.CrossRefGoogle ScholarPubMed
72. Sakakima, H, Khan, M, Dhammu, TS, et al. Stimulation of functional recovery via the mechanisms of neurorepair by S-nitrosoglutathione and motor exercise in a rat model of transient cerebral ischemia and reperfusion. Restor Neurol Neurosci. 2012;30:383-396.Google Scholar
73. Lee, MH, Kim, H, Kim, SS, et al. Treadmill exercise suppresses ischemia-induced increment in apoptosis and cell proliferation in hippocampal dentate gyrus of gerbils. Life Sci. 2003;73:2455-2465.CrossRefGoogle ScholarPubMed
74. Sim, YJ, Kim, H, Kim, JY, et al. Long-term treadmill exercise overcomes ischemia-induced apoptotic neuronal cell death in gerbils. Physiol Behav. 2005;84:733-738.CrossRefGoogle ScholarPubMed
75. Sim, YJ, Kim, SS, Kim, JY, Shin, MS, Kim, CJ. Treadmill exercise improves short-term memory by suppressing ischemia-induced apoptosis of neuronal cells in gerbils. Neurosci Lett. 2004;372:256-261.CrossRefGoogle ScholarPubMed
76. Ang, ET, Gomez-Pinilla, F. Potential therapeutic effects of exercise to the brain. Curr Med Chem. 2007;14:2564-2571.CrossRefGoogle ScholarPubMed
77. Poduslo, JF, Curran, GL. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res. 1996;36:280-286.CrossRefGoogle ScholarPubMed
78. Quirie, A, Hervieu, M, Garnier, P, et al. Comparative effect of treadmill exercise on mature BDNF production in control versus stroke rats. PLoS One. 2012;7:e44218.CrossRefGoogle ScholarPubMed
79. Ding, Q, Ying, Z, Gomez-Pinilla, F. Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing. Neuroscience. 2011;192:773-780.CrossRefGoogle ScholarPubMed
80. Griesbach, GS, Hovda, DA, Gomez-Pinilla, F. Exercise-induced improvement in cognitive performance after traumatic brain injury in rats is dependent on BDNF activation. Brain Res. 2009;1288:105-115.CrossRefGoogle ScholarPubMed
81. Sartori, CR, Vieira, AS, Ferrari, EM, et al. The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA. Neuroscience. 2011;180:9-18.CrossRefGoogle ScholarPubMed
82. Liu, N, Huang, H, Lin, F, et al. Effects of treadmill exercise on the expression of netrin-1 and its receptors in rat brain after cerebral ischemia. Neuroscience. 2011;194:349-358.CrossRefGoogle ScholarPubMed
83. Sun, J, Ke, Z, Yip, SP, Hu, XL, Zheng, XX, Tong, KY. Gradually increased training intensity benefits rehabilitation outcome after stroke by BDNF upregulation and stress suppression. Biomed Res Int. 2014;2014:925762.CrossRefGoogle ScholarPubMed
84. 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.CrossRefGoogle ScholarPubMed
85. Mizutani, K, Sonoda, S, Karasawa, N, et al. Effects of exercise after focal cerebral cortex infarction on basal ganglion. Neurol Sci. 2013;34:861-867.CrossRefGoogle ScholarPubMed
86. Ke, Z, Yip, SP, Li, L, Zheng, XX, Tam, WK, Tong, KY. The effects of voluntary, involuntary, and forced exercises on motor recovery in a stroke rat model. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:8223-8226.Google Scholar
87. Sun, J, Ke, Z, Yip, SP, Hu, XL, Zheng, XX, Tong, KY. Gradually increased training intensity benefits rehabilitation outcome after stroke by BDNF upregulation and stress suppression. Biomed Res Int. 2014;2014:925762.CrossRefGoogle ScholarPubMed
88. Kim, MW, Bang, MS, Han, TR, et al. Exercise increased BDNF and trkB in the contralateral hemisphere of the ischemic rat brain. Brain Res. 2005;1052:16-21.CrossRefGoogle ScholarPubMed
89. Chung, JY, Kim, MW, Bang, MS, et al. Increased expression of neurotrophin 4 following focal cerebral ischemia in adult rat brain with treadmill exercise. PLoS One. 2013;8:e52461.CrossRefGoogle ScholarPubMed
90. Chang, HC, Yang, YR, Wang, PS, et al. Insulin-like growth factor I signaling for brain recovery and exercise ability in brain ischemic rats. Med Sci Sports Exerc. 2011;43:2274-2280.CrossRefGoogle ScholarPubMed
91. Ohwatashi, A, Ikeda, S, Harada, K, et al. Exercise enhanced functional recovery and expression of GDNF after photochemically induced cerebral infarction in the rat. EXCLI J. 2013:693-700.Google ScholarPubMed
92. Llambi, F, Causeret, F, Bloch-Gallego, E, et al. Netrin-1 acts as a survival factor via its receptors UNC5H and DCC. EMBO J. 2001;20:2715-2722.CrossRefGoogle ScholarPubMed
93. Tang, X, Jang, SW, Okada, M, et al. Netrin-1 mediates neuronal survival through PIKE-L interaction with the dependence receptor UNC5B. Nat Cell Biol. 2008;10:698-706.CrossRefGoogle ScholarPubMed
94. Dent, EW, Barnes, AM, Tang, F, et al. Netrin-1 and semaphorin 3A promote or inhibit cortical axon branching, respectively, by reorganization of the cytoskeleton. J Neurosci. 2004;24:3002-3012.CrossRefGoogle ScholarPubMed
95. Wilson, BD, Ii, M, Park, KW, et al. Netrins promote developmental and therapeutic angiogenesis. Science. 2006;313:640-644.CrossRefGoogle ScholarPubMed
96. Sun, Y, Jin, K, Xie, L, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest. 2003;111:1843-1851.CrossRefGoogle ScholarPubMed
97. Slevin, M, Kumar, P, Gaffney, J, et al. Can angiogenesis be exploited to improve stroke outcome? Mechanisms and therapeutic potential. Clin Sci (Lond). 2006;111:171-183.CrossRefGoogle ScholarPubMed
98. Hayashi, T, Noshita, N, Sugawara, T, et al. Temporal profile of angiogenesis and expression of related genes in the brain after ischemia. J Cereb Blood Flow Metab. 2003;23:166-180.CrossRefGoogle ScholarPubMed
99. Beck, H, Acker, T, Wiessner, C, et al. Expression of angiopoietin-1, angiopoietin-2, and tie receptors after middle cerebral artery occlusion in the rat. Am J Pathol. 2000;157:1473-1483.CrossRefGoogle ScholarPubMed
100. Krupinski, J, Stroemer, P, Slevin, M, et al. Three-dimensional structure and survival of newly formed blood vessels after focal cerebral ischemia. Neuroreport. 2003;14:1171-1176.CrossRefGoogle ScholarPubMed
101. Jiang, Q, Zhang, ZG, Ding, GL, et al. Investigation of neural progenitor cell induced angiogenesis after embolic stroke in rat using MRI. Neuroimage. 2005;28:698-707.CrossRefGoogle ScholarPubMed
102. Hayashi, T, Deguchi, K, Nagotani, S, et al. Cerebral ischemia and angiogenesis. Curr Neurovasc Res. 2006;3:119-129.CrossRefGoogle ScholarPubMed
103. Manoonkitiwongsa, PS, Jackson-Friedman, C, Mcmillan, PJ, et al. Angiogenesis after stroke is correlated with increased numbers of macrophages: the clean-up hypothesis. J Cereb Blood Flow Metab. 2001;21:1223-1231.CrossRefGoogle ScholarPubMed
104. Petraglia, AL, Marky, AH, Walker, C, et al. Activated protein C is neuroprotective and mediates new blood vessel formation and neurogenesis after controlled cortical impact. Neurosurgery. 2010;66:165-172.CrossRefGoogle ScholarPubMed
105. Li, Q, Ford, MC, Lavik, EB, et al. Modeling the neurovascular niche: VEGF- and BDNF-mediated cross-talk between neural stem cells and endothelial cells: an in vitro study. J Neurosci Res. 2006;84:1656-1668.CrossRefGoogle ScholarPubMed
106. Wei, L, Erinjeri, JP, Rovainen, CM, et al. Collateral growth and angiogenesis around cortical stroke. Stroke. 2001;32:2179-2184.CrossRefGoogle ScholarPubMed
107. Krupinski, J, Kaluza, J, Kumar, P, et al. Role of angiogenesis in patients with cerebral ischemic stroke. Stroke. 1994;25:1794-1798.CrossRefGoogle ScholarPubMed
108. Arenillas, JF, Sobrino, T, Castillo, J, et al. The role of angiogenesis in damage and recovery from ischemic stroke. Curr Treat Options Cardiovasc Med. 2007;9:205-212.CrossRefGoogle ScholarPubMed
109. Ergul, A, Alhusban, A, Fagan, SC. Angiogenesis: a harmonized target for recovery after stroke. Stroke. 2012;43:2270-2274.CrossRefGoogle ScholarPubMed
110. Ma, Y, Qiang, L, He, M. Exercise therapy augments the ischemia-induced proangiogenic state and results in sustained improvement after stroke. Int J Mol Sci. 2013;14:8570-8584.CrossRefGoogle ScholarPubMed
111. Hu, X, Zheng, H, Yan, T, et al. Physical exercise induces expression of CD31 and facilitates neural function recovery in rats with focal cerebral infarction. Neurol Res. 2010;32:397-402.CrossRefGoogle ScholarPubMed
112. Zhang, P, Yu, H, Zhou, N, et al. Early exercise improves cerebral blood flow through increased angiogenesis in experimental stroke rat model. J Neuroeng Rehabil. 2013;10:43.CrossRefGoogle ScholarPubMed
113. Zheng, Q, Zhu, D, Bai, Y, et al. Exercise improves recovery after ischemic brain injury by inducing the expression of angiopoietin-1 and Tie-2 in rats. Tohoku J Exp Med. 2011;224:221-228.CrossRefGoogle ScholarPubMed
114. Gertz, K, Priller, J, Kronenberg, G, et al. Physical activity improves long-term stroke outcome via endothelial nitric oxide synthase-dependent augmentation of neovascularization and cerebral blood flow. Circ Res. 2006;99:1132-1140.CrossRefGoogle ScholarPubMed
115. Yang, YR, Chang, HC, Wang, PS, Wang, RY. Motor performance improved by exercises in cerebral ischemic rats. J Mot Behav. 2012;44:97-103.CrossRefGoogle ScholarPubMed
116. Tian, S, Zhang, Y, Tian, S, et al. Early exercise training improves ischemic outcome in rats by cerebral hemodynamics. Brain Res. 2013;1533:114-121.CrossRefGoogle ScholarPubMed
117. Liu, S, Wang, J, Zhu, D, et al. Generation of functional inhibitory neurons in the adult rat hippocampus. J Neurosci. 2003;23:732-736.CrossRefGoogle ScholarPubMed
118. van Praag, H, Schinder, AF, Christie, BR, et al. Functional neurogenesis in the adult hippocampus. Nature. 2002;415:1030-1034.CrossRefGoogle ScholarPubMed
119. Nakatomi, H, Kuriu, T, Okabe, S, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell. 2002;110:429-441.CrossRefGoogle ScholarPubMed
120. Font, MA, Arboix, A, Krupinski, J. Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke. Curr Cardiol Rev. 2010;6:238-244.CrossRefGoogle ScholarPubMed
121. Yiu, G, He, Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci. 2006;7:617-627.CrossRefGoogle ScholarPubMed
122. Rhodes, JS, van Praag, H, Jeffrey, S, et al. Exercise increases hippocampal neurogenesis to high levels but does not improve spatial learning in mice bred for increased voluntary wheel running. Behav Neurosci. 2003;117:1006-1016.CrossRefGoogle Scholar
123. Luo, CX, Jiang, J, Zhou, QG, et al. Voluntary exercise-induced neurogenesis in the postischemic dentate gyrus is associated with spatial memory recovery from stroke. J Neurosci Res. 2007;85:1637-1646.CrossRefGoogle ScholarPubMed
124. Mizutani, K, Sonoda, S, Yamada, K, et al. Alteration of protein expression profile following voluntary exercise in the perilesional cortex of rats with focal cerebral infarction. Brain Res. 2011;1416:61-68.CrossRefGoogle ScholarPubMed
125. Shih, PC, Yang, YR, Wang, RY. Effects of exercise intensity on spatial memory performance and hippocampal synaptic plasticity in transient brain ischemic rats. PLoS One. 2013;8:e78163.CrossRefGoogle ScholarPubMed
126. Schneider, A, Rogalewski, A, Wafzig, O, et al. Forced arm use is superior to voluntary training for motor recovery and brain plasticity after cortical ischemia in rats. Exp Transl Stroke Med. 2014;6:3.CrossRefGoogle ScholarPubMed
127. Chang, HC, Yang, YR, Wang, SG, Wang, RY. Effects of treadmill training on motor performance and extracellular glutamate level in striatum in rats with or without transient middle cerebral artery occlusion. Behav Brain Res. 2009;205:450-455.CrossRefGoogle ScholarPubMed
128. Mizutani, K, Sonoda, S, Wakita, H, Katoh, Y, Shimpo, K. Functional recovery and alterations in the expression and localization of protein kinase C following voluntary exercise in rat with cerebral infarction. Neurol Sci. 2014;35:53-59.CrossRefGoogle ScholarPubMed
129. Mizutani, K, Sonoda, S, Hayashi, N, et al. Analysis of protein expression profile in the cerebellum of cerebral infarction rats after treadmill training. Am J Phys Med Rehabil. 2010;89:107-114.CrossRefGoogle ScholarPubMed
130. Zheng, HQ, Zhang, LY, Luo, J, et al. Physical exercise promotes recovery of neurological function after ischemic stroke in rats. Int J Mol Sci. 2014;15:10974-10988.CrossRefGoogle ScholarPubMed
131. Gould, E, Beylin, A, Tanapat, P, et al. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci. 1999;2:260-265.CrossRefGoogle ScholarPubMed
132. Komitova, M, Zhao, LR, Gido, G, et al. Postischemic exercise attenuates whereas enriched environment has certain enhancing effects on lesion-induced subventricular zone activation in the adult rat. Eur J Neurosci. 2005;21:2397-2405.CrossRefGoogle ScholarPubMed
133. Yagita, Y, Kitagawa, K, Sasaki, T, et al. Postischemic exercise decreases neurogenesis in the adult rat dentate gyrus. Neurosci Lett. 2006;409:24-29.CrossRefGoogle ScholarPubMed
134. Lee, SH, Kim, YH, Kim, YJ, Yoon, BW. Enforced physical training promotes neurogenesis in the subgranular zone after focal cerebral ischemia. J Neurol Sci. 2008;269:54-61.CrossRefGoogle ScholarPubMed
135. Tang, Q, Yang, Q, Hu, Z, et al. The effects of willed movement therapy on AMPA receptor properties for adult rat following focal cerebral ischemia. Behav Brain Res. 2007;181:254-261.CrossRefGoogle Scholar
136. Tang, Q, Tan, L, Yang, X, et al. Willed-movement training reduces motor deficits and induces a PICK1-dependent LTD in rats subjected to focal cerebral ischemia. Behav Brain Res. 2013;256:481-487.CrossRefGoogle ScholarPubMed
137. Cheng, A, Hou, Y, Mattson, MP. Mitochondria and neuroplasticity. ASN Neuro. 2010;2:e00045.CrossRefGoogle ScholarPubMed
138. Garesse, R, Vallejo, CG. Animal mitochondrial biogenesis and function: a regulatory cross-talk between two genomes. Gene. 2001;263:1-16.CrossRefGoogle ScholarPubMed
139. Onyango, IG, Lu, J, Rodova, M, et al. Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta. 2010;1802:228-234.CrossRefGoogle ScholarPubMed
140. Valerio, A, Bertolotti, P, Delbarba, A, et al. Glycogen synthase kinase-3 inhibition reduces ischemic cerebral damage, restores impaired mitochondrial biogenesis and prevents ROS production. J Neurochem. 2011;116:1148-1159.CrossRefGoogle ScholarPubMed
141. Steiner, JL, Murphy, EA, Mcclellan, JL, et al. Exercise training increases mitochondrial biogenesis in the brain. J Appl Physiol. 1985;2011;111:1066-1071.CrossRefGoogle Scholar
142. Yin, W, Signore, AP, Iwai, M, et al. Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke. 2008;39:3057-3063.CrossRefGoogle ScholarPubMed
143. Bayod, S, Del, VJ, Canudas, AM, et al. Long-term treadmill exercise induces neuroprotective molecular changes in rat brain. J Appl Physiol. 1985;2011;111:1380-1390.CrossRefGoogle Scholar
144. Zhang, Q, Wu, Y, Sha, H, et al. Early exercise affects mitochondrial transcription factors expression after cerebral ischemia in rats. Int J Mol Sci. 2012;13:1670-1679.CrossRefGoogle ScholarPubMed
145. Zhang, Q, Wu, Y, Zhang, P, et al. Exercise induces mitochondrial biogenesis after brain ischemia in rats. Neuroscience. 2012;205:10-17.CrossRefGoogle ScholarPubMed
146. Wang, J, Feng, X, Du, Y, Wang, L, Zhang, S. Combination treatment with progesterone and rehabilitation training further promotes behavioral recovery after acute ischemic stroke in mice. Restor Neurol Neurosci. 2013;31:487-499.Google ScholarPubMed
147. Gherardini, L, Gennaro, M, Pizzorusso, T. Perilesional treatment with chondroitinase ABC and motor training promote functional recovery after stroke in rats. Cereb Cortex. 2015;25:202-212.CrossRefGoogle ScholarPubMed
148. Li, L, Rong, W, Ke, Z, Hu, X, Tong, KY. The effects of training intensities on motor recovery and gait symmetry in a rat model of ischemia. Brain Inj. 2013;27:408-416.CrossRefGoogle Scholar
149. Austin, MW, Ploughman, M, Glynn, L, Corbett, D. Aerobic exercise effects on neuroprotection and brain repair following stroke: a systematic review and perspective. Neurosci Res. 2014;87:8-15.CrossRefGoogle ScholarPubMed
Figure 0

Table 1 References of early exercise after stroke