Abstract
Stroke treatment is limited to time-critical thrombectomy and rehabilitation by physiotherapy. Studies report beneficial effects of exercise; however, a knowledge gap exists regarding underlying mechanisms that benefit recovery of brain networks and cognition. This study aims to unravel therapeutic effects of voluntary exercise in stroke-induced mice to develop better personalized treatments. Male C57Bl6/JOlaHsd mice were subjected to transient middle cerebral artery occlusion. After surgery, the animals were divided in a voluntary exercise group with access to running wheels (RW), and a control group without running wheels (NRW). During 6 days post-stroke, activity/walking patterns were measured 24/7 in digital ventilated cages. Day 7 post-surgery, animals underwent MRI scanning (11.7T) to investigate functional connectivity (rsfMRI) and white matter (WM) integrity (DTI). Additionally, postmortem polarized light imaging (PLI) was performed to quantify WM fiber density and orientation. After MRI the animals were sacrificed and neuroinflammation and cerebral vascularisation studied. Voluntary exercise promoted myelin density recovery corresponding to higher fractional anisotropy. The deteriorating impact of stroke on WM dispersion was detected only in NRW mice. Moreover, rsfMRI revealed increased functional connectivity, cerebral blood flow and vascular quality leading to improved motor skills in the RW group. Furthermore, voluntary exercise showed immunomodulatory properties post-stroke. This study not only helped determining the therapeutic value of voluntary exercise, but also provided understanding of pathological mechanisms involved in stroke.
Highlights
Stroke is the fifth leading cause of death and the leading cause of long-term disability in the US in 2020 (Ahmad and Anderson, 2021; Jaillard, 2021)
We have shown in 3 months old stroke mice, resembling mature adult humans (Flurkey and Harrison, 2007), that even short-term (1 week) voluntary exercise positively influenced the recovery in experimental stroke mice
Since the presented short-term voluntary exercise paradigm already resulted in promising therapeutic effects, we suggest to further elucidate the impact of voluntary exercise on stroke recovery longitudinally, including additional motor and behavioral tests (e.g., Bederson score, elevated body swing test)
Summary
Stroke is the fifth leading cause of death and the leading cause of long-term disability in the US in 2020 (Ahmad and Anderson, 2021; Jaillard, 2021). Management of ischemic stroke focuses primarily on time critical thrombolysis, recanalization therapy and treatment of symptoms (Sehatzadeh, 2015; Hankey, 2017). Efficacy of available therapies is insufficient considering the high number of stroke survivors suffering from persistent symptoms, like disability (40%) (Hankey, 2017). Drugs based on other mechanisms, like neuroprotectants, failed clinical trials (Chen and Wang, 2016). Alternatives to pharmacotherapeutic treatments are urgently needed (Chen and Wang, 2016)
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