In Search of a Dose: The Functional and Molecular Effects of Exercise on Post-stroke Rehabilitation in Rats

Abstract

Although physical exercise has been demonstrated to augment recovery of the post-stroke brain, the question of what level of exercise intensity optimizes neurological outcomes of post-stroke rehabilitation remains unsettled. In this study, we aim to clarify the mechanisms underlying the intensity-dependent effect of exercise on neurologic function, and thereby to help direct the clinical application of exercisebased neurorehabilitation. To do this, we used a well-established rat model of ischemic stroke consisting of cerebral ischemia induction through middle cerebral artery occlusion (MCAO). Ischemic rats were subsequently assigned either to a control group entailing post-stroke rest or to one of two exercise groups distinguished by the intensity of their accompanying treadmill regimens. After 24 h of reperfusion, exercise was initiated. Infarct volume, apoptotic cell death, and neurological defects were quantified in all groups at 3 days, and motor and cognitive functions were tracked up to day-28. Additionally, Western blotting was used to assess the influence of our interventions on several proteins related to synaptogenesis and neuroplasticity (growth-associated protein 43, a microtubule-associated protein, postsynaptic density-95, synapsin I, hypoxia-inducible factor-1α, brain-derived neurotrophic factor, nerve growth factor, tyrosine kinase B, and cAMP response element-binding protein). Our results were in equal parts encouraging and surprising. Both mild and intense exercise significantly decreased infarct volume, cell death, and neurological deficits. Motor and cognitive function, as determined using an array of tests such as beam balance, forelimb placing, and the Morris water maze, were also significantly improved by both exercise protocols. Interestingly, while an obvious enhancement of neuroplasticity proteins was shown in both exercise groups, mild exercise rats demonstrated a stronger effect on the expressions of Tau (p < 0.01), brain-derived neurotrophic factor (p < 0.01), and tyrosine kinase B (p < 0.05). These findings contribute to the growing body of literature regarding the positive effects of both mild and intense long-term treadmill exercise on brain injury, functional outcome, and

Effects of Aerobic Exercise on Tau and Related Proteins in Rats with the Middle Cerebral Artery Occlusion

“…Further, in the brain, the p-tau was more prominent in the hippocampus rather than the cortex [ 15 ]. The most recent study demonstrated that mild and intense exercise training for up to 28 days reduced infarct volume and improved brain function in the rat MCAO model [ 14 ]. Interestingly, the levels of tau protein and brain-derived neurotropic factor (BDNF) were higher in the mild aerobic exercise group than the intense training group, which suggests the variability in the effects of exercise on tau-related pathology according to the intensity, type, and duration of exercise [ 14 ].…”

“…In human stroke, reperfusion by thrombolytic drugs produce ischemic penumbra, which is potentially a salvageable area where neural plasticity takes place with rehabilitation [12]. While PIT infarction makes cell apoptosis and clear infarction margins with no penumbra, the reperfusion process followed by occlusion with MCAO could make a penumbra area, mimicking the human ischemic stroke pathophysiology more [13]; a recent study reported that exercise improved the expression of neuroplasticity proteins including tau and brain-derived neurotrophic factor (BDNF) in a MCAO model of rats [14].…”

Effect of Different Exercise Intensity Preconditioning on Global Ischemia-Induced Neuronal Death and Expression of Gadd45β and DNA-PKcs in Rats

“…As Shown by Linder et al, higher intensity exercise can promote functional recovery and neuroplasticity after stroke [13][14][15]. Other studies have shown that mild exercise can improve neuroprotection and synaptic plasticity after stroke [16]. These conflicting results underscore that exercise intensity is an important determinant of neurological outcomes after stroke.…”

Mini review (Part I): An experimental concept on exercise and ischemic conditioning in stroke rehabilitation

“…[ 10 ] Our study recently suggested that the beneficial effect of intense exercise was not superior than its milder counterpart, thus mild exercise may be adequate and sufficient to elicit neurorehabilitation poststroke. [ 28 ] Our previous study underlined that too early poststroke exercise increased cell stress and expression of pro-inflammatory cytokines, which amplified tissue damage, and suggests that exercise interventions between 24 h and 3 days may optimize rehabilitation benefit. [ 29 ] In addition, Yagita et al .…”