Exacerbation of Brain Injury by Post-Stroke Exercise Is Contingent Upon Exercise Initiation Timing

Abstract

Accumulating evidence has demonstrated that post-stroke physical rehabilitation may reduce morbidity. The effectiveness of post-stroke exercise, however, appears to be contingent upon exercise initiation. This study assessed the hypothesis that very early exercise exacerbates brain injury, induces reactive oxygen species (ROS) generation, and promotes energy failure. A total of 230 adult male Sprague-Dawley rats were subjected to middle cerebral artery (MCA) occlusion for 2 h, and randomized into eight groups, including two sham injury control groups, three non-exercise and three exercise groups. Exercise was initiated after 6 h, 24 h and 3 days of reperfusion. Twenty-four hours after completion of exercise (and at corresponding time points in non-exercise controls), infarct volumes and apoptotic cell death were examined. Early brain oxidative metabolism was quantified by examining ROS, ATP and NADH levels 0.5 h after completion of exercise. Furthermore, protein expressions of angiogenic growth factors were measured in order to determine whether post-stroke angiogenesis played a role in rehabilitation. As expected, ischemic stroke resulted in brain infarction, apoptotic cell death and ROS generation, and diminished NADH and ATP production. Infarct volumes and apoptotic cell death were enhanced (p < 0.05) by exercise that was initiated after 6 h of reperfusion, but decreased by late exercise (24 h, 3 days). This exacerbated brain injury at 6 h was associated with increased ROS levels (p < 0.05), and decreased (p < 0.05) NADH and ATP levels. In conclusion, very early exercise aggravated brain damage, and early exercise-induced energy failure with ROS generation may underlie the exacerbation of brain injury. These results shed light on the manner in which exercise initiation timing may affect post-stroke rehabilitation.

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

“…Specifically, we showed that both mild and intense exercise regimens reduced brain infarct volume and apoptotic cell death, and improved motor and cognitive function at 3, 14, and 28 days after ischemia/reperfusion injury. The early improvement in infarct volume seen in these results aligned with a previous meta-analysis, in which infarct volume was reduced most effectively by exercise administered with the shortest delays after ischemia (Egan et al, 2014 ); data from our group derived from pre-conditioning experimentation suggest that this may be related to the capacity of exercise to mitigate inflammatory damage during reperfusion (Ding et al, 2005 ), with the caveat that the exercise initiation too early after ischemia may be detrimental (Li et al, 2017a ). More recent work by our group further substantiated these findings by demonstrating that exercise improved glycometabolism in the ischemic area and decreased neuroinflammation and apoptosis as early as 1 day post-stroke, and also at 3 days (Shen et al, 2016 ; Li et al, 2017a , b , c ).…”

“…In this study, we intended to observe the protective effects of post-stroke exercise on brain infarct at 3 days as previous studies did. Recent work by our group substantiates these findings by demonstrating exercise-improved glycometabolism, decreased neuroinflammation, and apoptosis (Li et al, 2017a , b , c ). The present results were largely supported by the findings of other groups, which demonstrated that exercise accelerated CBF (Pianta et al, 2019 ), decreased infarct volume (Tian et al, 2013 ; Zhang Y. et al, 2013 ; Pan et al, 2020 ) and improved functional outcomes (Pianta et al, 2019 ).…”

“…To agree with the principle that a physical exercise regimen is reproducible (Gronwald et al, 2019 ), our further exercise procedure would focus on a physiological indicator such as the lactate threshold. Another key finding from our previous work was the influence of initiation time on post-stroke rehabilitation outcomes: initiation 6 h post-stroke exacerbated brain damage, but this was avoided when exercise was deferred for 1–3 days (Li et al, 2017a , b ). Therefore, the initiation time of 24 h after stroke was selected in this study.…”

Combining robotic training and inactivation of the healthy hemisphere restores pre-stroke motor patterns in mice

“…The early imbalance in interhemispheric connectivity following stroke ( Figure 1 ) suggested us a prompt inactivation of the contralesional cortex via BoNT/E, which requires at least 24 hr to become fully active ( Antonucci et al, 2008 ). For robotic training, we chose to start the physiotherapy at day 5, since it is known that early exercise may exacerbate brain injury, via excitotoxicity and generation of reactive oxygen species ( Kozlowski et al, 1996 ; Li et al, 2017 ). Moreover, it is widely believed that priming the brain with a ‘plasticity-stimulating’ treatment before the beginning of a rehabilitative treatment improves motor performance after brain lesions ( Schäbitz et al, 2004 ; Starkey et al, 2012 ; Wahl et al, 2014 ).…”

Prevalence of Low Plasma Vitamin B1 in the Stroke Population Admitted to Acute Inpatient Rehabilitation

“…Defining and identifying this association is the first step in further investigating if the repletion of VitB1 in these patients during their continuum of care may play a role in optimizing their recovery. This latter point may be most important given the increased metabolic demands of the brain at baseline and especially post-stroke [45], similar to the increased metabolic demand seen in the VitB1 deficiency of chronic alcoholics [46]. The increased metabolic demand post-stroke was observed as early as the 1970s by investigators reporting an increase of up to 100% in energy requirements of patients with hemiparetic gait [47,48].…”