Enhanced apoptosis from early physical exercise rehabilitation following ischemic stroke
Postinjury exercise therapy that aims to ameliorate physical disability after stroke has long been considered a logical candidate for neuroprotective rehabilitation (Arya et al., 2011). In previous studies, neuroprotection has been consistently evidenced by physical exercise through reduced sequelae of brain infarction with improved functional outcomes in a rat ischemic stroke model (Ding et al., 2006; Dornbos et al., 2013; Q.W. Zhang et al., 2013). With experimental animal models of stroke, some studies have suggested a beneficial effect of exercise initiated as early as 24 hr after the onset of ischemic or hemorrhagic stroke (Park et al., 2010; Matsuda et al., 2011; P. Zhang et al., 2013). Furthermore, only mild to moderate but not heavy exercise, if initiated early, is thought to promote recovery from ischemic stroke in rats (Lee et al., 2009). In contrast, training initiated 24 hr after permanent focal brain ischemia was found to exacerbate cortical tissue loss (Humm et al., 1998; Risedal et al., 1999). Furthermore, increased injury was detected in the forelimb area within the sensorimotor cortex of rats that were forced to overuse the impaired forelimb for 7 or 15 days postischemic stroke (Kozlowski et al., 1996; Humm et al., 1998). Together these studies highlight the importance of exercise timing poststroke with regard to recovery from injury and physical disability.
The molecular underpinnings of apoptotic cell death following cerebral ischemia are well established. During periods of reduced oxygen delivery, proapoptotic proteins, such as caspase‐3 and BAX, become upregulated and are one of the major causes of neuronal death during ischemia/reperfusion injury (Wu et al., 2003). Conversely, Bcl‐2 is an antiapoptotic protein that plays a critical role in cellular survival by acting as a repressor of apoptosis (Korsmeyer, 1995). Thus, the aim of the present study was to determine the effect of physical exercise therapy on apoptotic cell death and the expression of associated pro‐ and antiapoptotic proteins. We directly compared the effect of poststroke exercise on brain injury at 6 hr, 24 hr, and 3 days after reperfusion with the corresponding nonexercise group. Following a 2‐hr middle cerebral artery occlusion (MCAO), we evaluated the extent of apoptotic cell death and the expression of proapoptotic (caspase‐3 and BAX) and antiapoptotic (Bcl‐2) proteins.