Perspectives on rehabilitation, exercise and synaptogenesis after stroke

Chaitu Dandu; Fengwu Li; Yuchuan Ding

doi:10.4103/2773-2398.372308

REVIEW

Year : 2023 | Volume : 2 | Issue : 1 | Page : 21-24

Perspectives on rehabilitation, exercise and synaptogenesis after stroke

Chaitu Dandu¹, Fengwu Li², Yuchuan Ding¹
¹ Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA
² China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China

Date of Submission	23-Aug-2022
Date of Decision	06-Dec-2022
Date of Acceptance	14-Mar-2023
Date of Web Publication	28-Mar-2023

Correspondence Address:
Yuchuan Ding
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI
USA

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2773-2398.372308

Abstract

Strokes are a leading cause of death, persistent neurological deficits, and physical disability worldwide. Exercise-mediated adaptations are an emerging form of therapies that aim to attenuate the severity of post-stroke physical disability; however, there are uncertainties regarding how specific parameters, such as time to initiation and intensity of exercise, affect rehabilitation outcomes. At the cellular level, physical rehabilitation after stroke may enhance post-stroke gluconeogenesis to promote neuroplasticity over cellular damage via hypoxia-inducible factor-1α and exosomes. Furthermore, there is thought to be an optimal time for the initiation of exercise after a stroke, but there is disagreement and uncertainty about this optimal time. This paper discusses the pathophysiology of physical rehabilitation after stroke and reviews current studies on the effects of physical exercise on stroke rehabilitation and plasticity.

Keywords: exosomes; gluconeogenesis; neuroplasticity; physical rehabilitation; transcription factor

How to cite this article:
Dandu C, Li F, Ding Y. Perspectives on rehabilitation, exercise and synaptogenesis after stroke. Brain Netw Modulation 2023;2:21-4

How to cite this URL:
Dandu C, Li F, Ding Y. Perspectives on rehabilitation, exercise and synaptogenesis after stroke. Brain Netw Modulation [serial online] 2023 [cited 2023 Jun 4];2:21-4. Available from: http://www.bnmjournal.com/text.asp?2023/2/1/21/372308

Introduction

Stroke claims approximately 15 million victims worldwide each year and is the leading cause of persistent neurological deficits and profound physical disability (Persky et al., 2010). In neurotherapeutics, exercise-mediated adaptations are emerging therapies that aim to reduce the severity of physical disability after stroke. However, there is disagreement and uncertainty regarding how specific parameters of exercise-mediated adaptions, such as time to initiation and intensity of exercise, affect rehabilitation outcomes. Although current guidelines recommend initiating out-of-bed activity “early” during the acute phase of care, they do not provide a rationale for why early exercise after stroke optimizes outcomes (AVERT Trial Collaboration group, 2015). On the other hand, the literature presents a conflicting picture regarding the beneficial effect(s) of early exercise after stroke. Some studies suggest that very early activity exacerbates brain damage (AVERT Trial Collaboration group, 2015; Cumming et al., 2018, 2019). A recent literature review of exercise after stroke demonstrates that the pro-plasticity effects of exercise to optimize behavioral outcome after stroke are well-documented (Hugues et al., 2021). Rehabilitative exercise strategies, such as physical activity and spatial learning, activate neuroplastic chemical and morphological changes in the brain that are key to behavioral rehabilitation. Compared to performing simple tasks, complex motor skill training improves functional performance and enhances cortical synaptogenesis in normal rats and rats with damage to the forelimb sensorimotor cortex (Shih et al., 2013). A parsimonious interpretation of these conflicting results shows that there is an opportunity to enhance exercise-based, use-dependent synaptogenesis for optimal outcomes after stroke (Li et al., 2020). This mini-review focuses on physical rehabilitation, exosomes, transcription factor, gluconeogenesis, and neuroplasticity after stroke. We mainly search for the most relevant publications through PubMed for the last 15 years.

Pathophysiology underlying stroke rehabilitation

Stroke results in diverse pathophysiology that contributes to cell injury and behavioral deficits. Energy failure and oxidative stress are basic mechanisms that lead to cell injury and death, which underlie poor behavioral outcomes. Physical exercise is assumed to impose higher metabolic demand on brain tissue injured by stroke. However, given that studies show that exercise after stroke improves outcomes (Bernhardt, 2008), this suggests there is a balance between exercise-induced higher metabolic demand, which exacerbates oxidative cell injury, and exercise-induced initiation of neuroplasticity, which leads to functional recovery (AVERT Trial Collaboration group, 2015). Glucose is the primary energy source for neuronal activity and is initially catabolized by glycolysis. The products formed from the breakdown of glucose are then eventually shunted through the aerobic pathway to produce the bulk of cellular adenosine triphosphate. However, during ischemia, when oxidative phosphorylation of glucose is impaired due to oxygen deprivation, brain cells attempt to meet this metabolic challenge by increasing anaerobic glycolysis (or hyperglycolysis) (Schurr, 2002), resulting in lactic acidosis and increased reactive oxygen species, especially upon reperfusion. However, evidence suggests that there may be other factors involved, as, patients continue to have poor outcomes even when hyperglycolysis is under control in clinical settings (Ginsberg, 2002; Bruno et al., 2008). One factor that may contribute to poor outcomes, in spite of hyperglycolysis control, is dysfunctional gluconeogenesis that occurs in the brain after an ischemic stroke (Geng et al., 2021). Dysfunctional gluconeogenesis during stroke has the potential to exacerbate acidosis and increase reactive oxygen damage. Due to the lack of adenosine triphosphate during ischemia, gluconeogenesis is stunted, leading to accumulation of phosphoenolpyruvate that is facilitated by phosphoenolpyruvate carboxykinase. In turn, phosphoenolpyruvate serves as a source for lactic acidosis and thus reactive oxygen species production, rather than glucose production. Hypoxia-inducible factors are transcription factors that are activated in response to a decline in cellular oxygen (Wilkins et al., 2016). Reactive and incomplete gluconeogenesis has been linked to hypoxia-inducible factor 1-α transcriptional regulation (Owczarek et al., 2020). Hypoxia-inducible factor 1-α induced by ischemia acts in synergy with the active form of the endoplasmic reticulum stress-inducible transcription factor X-box binding protein 1 (Chaudhari et al., 2014), which interacts with forkhead box O transcription factor to regulate gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (Zhou et al., 2011; Zhang et al., 2014; Cao et al., 2018), as well as synaptic plasticity (Xia et al., 2018). Regarding synaptic plasticity, there is emerging evidence suggesting that exosomes may contribute to facilitating synaptogenesis (Yamada and Jinno, 2019). Furthermore, in a study conducted by Li et al. (2021), exercise following a stroke in mouse models of middle cerebral artery occlusion was associated with increased serum exosome levels, which in turn were associated with increased numbers of synapses, synaptophysin, and postsynaptic density protein 95, all markers for synaptic generation.

Post-stroke gluconeogenesis may serve as a weight to tip the balance toward neuroplasticity and away from cell damage during post-stroke physical exercise, thus serving as a basis for improved exercise rehabilitation after stroke. The survival rate of stroke patients has significantly increased over the last decade due to advances in medical technology. However, most survivors still suffer from irreversible brain damage and the accompanying long-term disabilities, including impaired motor, communication, and cognition (Knecht et al., 2011). Stroke remains the leading cause of significant long-term disability. To reduce the catastrophic impact on stroke patients and their families, as well as the burden imposed on society, stroke research should not only focus on decreasing the incidence and severity of stroke, but also on improving post-stroke outcomes with patient rehabilitation. Providing physicians and patients with appropriate recommendations is critical to successfully advocating exercise rehabilitation for optimal recovery after stroke.

Stroke rehabilitation by exercise

Although the positive effects of exercise after stroke have been widely acknowledged in stroke patients, there is no optimal rehabilitation protocol for improving functional recovery in the clinical setting (Arya et al., 2011). Current rehabilitation models do not reverse physical deconditioning or optimize motor function by providing inadequate exercise or sufficient task repetition (Stinear et al., 2020). It has been well-recognized that improving functional recovery after brain injury is time-sensitive (Hsu and Jones, 2005). Thus, there is a window of opportunity after stroke to enhance use-dependent neuroplastic structural and functional changes for optimal recovery. Current rehabilitation models do not reverse physical deconditioning nor optimize motor function due to providing inadequate exercise or sufficient task repetition, respectively. The A Very Early Rehabilitation Trial (AVERT) trial revealed that early mobilization within 24 hours of stroke onset did not result in a difference in cognitive outcomes between the early mobilization group and non-early mobilization group (Cumming et al., 2019). In addition, the authors of the trial failed to make a recommendation regarding specific initiation time for rehabilitation. Interestingly, animal models of stroke have suggested potential benefits from exercise started within 24 hours after stroke (Matsuda et al., 2011; Zhang et al., 2013) or cerebral hemorrhage (Risedal et al., 1999; Park et al., 2010). However, if initiation of physical activity is too early, there is a negative impact on functional recovery, lesion volume, and the levels of the proteins that mediate plasticity during neuroregeneration (Humm et al., 1998; Risedal et al., 1999). Conversely, when physical activity is initiated 5–6 months after stroke, there is also no improvement in physical or cognitive outcomes (Koch et al., 2020). Thus, there is a need to identify an adequate time frame for the initiation of stroke rehabilitation. In addition, there is also a need to identify the types of exercises performed. It has been revealed that compared to performing simple repetitive exercises, complex motor skill training enhances cortical synaptogenesis and improves functional performance in both normal rats and rats with prior forelimb sensorimotor cortex damage (Shih et al., 2013). Another study indicated that only mild to moderate, but not intense, early exercises promoted recovery from ischemic stroke in rats (Lee et al., 2009). As we have established, the results from the prior studies clearly show that the initiating time, exercise type, and exercise intensity affect post-stroke rehabilitation outcomes.

Synaptic plasticity enhanced by exercise

Findings from both human and animal studies indicate that physical activity and exercise play a role in promoting neuroplasticity and enhancing functional outcomes (Xing and Bai, 2020). Neuroplastic changes following exercise include promotion of cell proliferation, neurogenesis, angiogenesis, and elevation of neurotrophic factors leading to repair and restorative effects (Dornbos and Ding, 2012). Synaptic plasticity following exercise will thus be used as a marker of brain recovery in the present study. Post-stroke brain remodeling through synaptogenesis can establish new synaptic connections to compensate for those lost. To facilitate these new synaptic connections, task-specific and repetitive exercises can play a key role (O'Dell et al., 2009). Synaptogenesis and the formation of new circuits are the underpinnings in rehabilitating patients with motor weakness following stroke. Animal studies of training and rehabilitation after stroke have shown a correlation between increased neuronal plasticity and functional recovery (Dimyan and Cohen, 2011; Jo and Perez, 2020). The overarching aim of our community is to develop a viable rehabilitative strategy for all stroke patients. Understanding the molecular mechanisms by which different exercise regimens influence stroke outcomes will allow for a more comprehensive evaluation of optimal stroke rehabilitation therapies. If future studies focus on studying not only behavioral outcomes but also histological and cellular outcomes, it will be easier to determine how post-stroke exercise can be beneficial without the currently known detrimental effects. Our future studies will investigate how exercise can stimulate neuroplasticity as well as ameliorate incomplete gluconeogenesis and its downstream effects, in the hope of producing clinically transformative outcomes.

Conclusion

Despite nearly two decades of research and novel therapeutics in the United States, patients with acute ischemic stroke still experience significant neurological and physician disability even after treatment with reperfusion strategies, such as thrombolysis and interventional thrombectomy. As such, stroke remains a leading cause of lasting neurological deficits and profound physical disability. However, there has been a relative lack of development and research into post-stroke rehabilitation compared to stroke therapeutics. Furthermore, current research provides conflicting opinions on how early patients should start rehabilitative exercises after stroke. Our long-term efforts are to establish an optimal evidence-based exercise protocol for optimized physical recovery after stroke. Optimized physical recovery after stroke will define and pay special attention to the timing, type, and intensity of exercise, which will be dependent on the patient’s physical disabilities. The protocol will be backed by the analysis of underlying cellular and molecular mechanisms and be adjusted as needed to optimize exercise rehabilitation after stroke.

Author contributions

All authors conceived and drafted the manuscript, made critical revision, and reviewed and approved the final version of the manuscript.

Conflicts of interest

There are no conflicts of interest.

Data availability statement

All relevant data are within the paper.

open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.[37]

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