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. 2019 Jul;14(7):1230-1236.
doi: 10.4103/1673-5374.251330.

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

Min Cheol Chang  1 , Chae Ri Park  2 , Seung Hwa Rhie  3 , Woo Hyun Shim  4 , Dae Yul Kim  3
Affiliations

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

Min Cheol Chang et al. Neural Regen Res. 2019 Jul.

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).

Keywords: brain-derived neurotrophic factor; early exercise; ischemic stroke; macrophage migration inhibitory factor; motor recovery; neural regeneration.

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Conflict of interest statement

None

Figures

Figure 1
Figure 1
Magnetic resonance images after ischemia/reperfusion modeling. (A) T2-weighted magnetic resonance image of a rat subjected to middle cerebral artery occlusion. (B) Four regions of interest (ROIs) were drawn on the diffusion magnetic resonance image. R: Right; L: left.
Figure 2
Figure 2
Results of the wire hang test of rats. (A) Wire hang test. The rat was placed on a wire bar and inverted 180°. (B) Results of the wire hang test at 24 hours and 7 days after reperfusion for the Sham-Ex (n = 10), Sham-St (n = 10), MCAO-Ex (n = 10), and MCAO-St groups (n = 10). This test was repeated 5 times with an interval of 3 minutes between trials. The mean latency to fall in the five trials was determined. *P < 0.05 (independent samples t-test). Sham-Ex group: Sham-surgery and exercise group; Sham-St group: sham-surgery and sedentary group; MCAO-Ex group: the ischemia and exercise group; MCAO-St group: ischemia and sedentary group; MCAO: middle cerebral artery occlusion.
Figure 3
Figure 3
Changes in the rFA in rats after treadmill exercise. (A) Changes in the rFA in the peri-infarct region at 24 hours and 7 days after reperfusion for all groups. (B) Changes in the rFA in the ischemic core at 24 hours and 7 days after reperfusion for all groups. *P < 0.05 (independent samples t-test). Sham-Ex group: Sham-surgery and exercise group; Sham-St group: sham-surgery and sedentary group; MCAO-Ex group: the ischemia and exercise group; MCAO-St group: ischemia and sedentary group; MCAO: middle cerebral artery occlusion; rFA: relative fractional anisotropy.
Figure 4
Figure 4
Immunohistochemical findings of MIF in the peri-infarct region (A) and ischemic core (B) in rats at 7 days after reperfusion. *P < 0.05 (independent samples t-test). MCAO: Middle cerebral artery occlusion; Mag: magnification; MIF: macrophage migration inhibitory factor.
Figure 5
Figure 5
Immunohistochemical findings of BDNF in the peri- infarct region (A) and ischemic core (B) in rats at 7 days after reperfusion. Data are expressed as the mean ± SD from n = 10 per group. *P < 0.05 (independent samples t-test). MCAO: Middle cerebral artery occlusion; Mag: magnification; BDNF: brain-derived neurotrophic factor.
Figure 6
Figure 6
Correlation between the rFA and immunohistochemical results in the peri-infarct region. The rFA values in the peri-infarct region of rats subjected to middle cerebral artery occlusion (MCAO) showed a significant positive correlation with the expression levels of macrophage migration inhibitory factor (MIF; A) and brain-derived neurotrophic factor (BDNF; B) in the peri-infarct region (Pearson’s correlation analysis). MCAO-Ex group: the ischemia and exercise group; MCAO-St group: ischemia and sedentary group; rFA: relative fractional anisotropy.
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