Early treadmill exercise increases macrophage migration inhibitory factor expression after cerebral ischemia/reperfusion

Abstract

The neuroprotective function of macrophage migration inhibitory factor (MIF) in ischemic stroke was rarely evaluated. This study aimed to investigate the effects of early treadmill exercise on recovery from ischemic stroke and to determine whether these effects are associated with the expression levels of MIF and brain-derived neurotrophic factor (BDNF) in the ischemic area. A total of 40 male Sprague-Dawley rats were randomly assigned to the ischemia and exercise group [middle cerebral artery occlusion (MCAO)-Ex, n = 10), ischemia and sedentary group (MCAO-St, n = 10), sham-surgery and exercise group (Sham-Ex, n = 10), or sham-surgery and sedentary group (Sham-St, n = 10). The MCAO-Ex and MCAO-St groups were subjected to MCAO for 60 minutes, whereas the Sham-Ex and Sham-St groups were subjected to an identical operation without MCAO. Rats in the MCAO-Ex and Sham-Ex groups then ran on a treadmill for 30 minutes once a day for 5 consecutive days. After reperfusion, the hanging time tested by the wire hang test was longer and the relative fractional anisotropy determined by MRI was higher in the peri-infarct region of the MCAO-Ex group compared with the MCAO-St group. The expression levels of MIF and BDNF in the peri-infarct region were upregulated in the MCAO-Ex group. Increased MIF and BDNF levels were positively correlated with relative fractional anisotropy changes in the peri-infarct region. There was no significant difference in the levels of MIF and BDNF in the peri-infarct region between the Sham-Ex and Sham-St groups. Our study demonstrated that early exercise (initiated 48 hours after the MCAO) could improve motor and neuronal recovery after ischemic stroke. Furthermore, the increased levels of MIF and BDNF in the peri-infarct region (penumbra) may be one of the mechanisms of enhanced neurological function recovery. All experiments were approved by the Institutional Animal Care and Use Committee in Asan Medical Center in South Korea (2016-12-126).

Determining the Optimal Administration Conditions under Which MIF Exerts Neuroprotective Effects by Inducing BDNF Expression and Inhibiting Apoptosis in an In Vitro Stroke Model

“…This signaling mainly suppresses c-Jun N-terminal kinase activation, leading to inhibited apoptosis [ 13 , 17 ]. In addition, MIF exerts neuroprotective effects by inducing BDNF [ 22 , 23 , 26 ], which may be mediated via the CD74–ERK1/2 pathway [ 26 ]. Specifically, a pre-pro form of BDNF protein is first synthesized followed by subsequent removal of the pro-region [ 24 ].…”

“…Our previous studies have reported that MIF mainly plays a neuroprotective role in ischemic stroke [ 22 , 23 ]. In these studies, we found that MIF was neuroprotective in ischemic stroke models via the inhibition of neuronal cell apoptosis and induction of brain-derived neurotrophic factor (BDNF) expression.…”

Novel Mechanisms of Exercise-Induced Cardioprotective Factors in Myocardial Infarction

“…This finding suggests a potential therapeutic role of MIF in the treatment of MI (Cui et al, 2016). Additionally, MIF expression can also be induced by exercise, and it has been identified as an exercise-induced cardioprotective factor that protects against MI (Chang et al, 2019).…”

Treadmill Exercise Attenuates Cerebral Ischemia–Reperfusion Injury by Promoting Activation of M2 Microglia via Upregulation of Interleukin-4

“…Clinically, early exercise has been proven to be an effective method to promote motor recovery in patients with ischemic stroke (1,2). Experimental studies have also demonstrated that treadmill training is beneficial in ameliorating neurological deficits in rats after cerebral ischemia (3,4). Further analysis of the mechanism of exercise-induced neuroprotection revealed decreased activation of resident cells such as microglia and astrocytes (5,6), suppressed expression of pro-inflammatory cytokines (6,7), and reduced leukocyte infiltration in the penumbra (8,9), results consistent with our previous findings (10).…”