Table 1.
Methodological characteristics and main results of studies that evaluated the effects of physical activity on the BDNF levels post-stroke.
| Article | Sample size | Characteristics of Injury | Characteristics of the sample | Methodology of measurement | Site of measurement | Protocol of exercise | Instruments of motor assessment | Time between measurements | Main results | |
|---|---|---|---|---|---|---|---|---|---|---|
| Type (mechanism) | Time post-injury | |||||||||
| AEROBIC EXERCISE | ||||||||||
| (14) | Exercice (n = 18) Non-exercice (n = 17) Sham (n = 12) |
Ischemic Middle Cerebral Artery Occlusion | 4 days | Sprague-Dawley Rats | Western Blotting Immunohistochemistry |
Systemic: — — Central: ipsilateral and contralateral |
Treadmill: For 12 days at 30 min per day. Initial velocity was 10 m/min and velocity progression was 5 m/min per week. |
Motor behavior index | Behavioral test: 2, 9, 16 days post-stroke BDNF: 16 days post stroke |
Treadmill exercise for 2 weeks promoted motor function and changed the expressions of BDNF and trkB proteins. The expressions of BDNF and full-length trkB were increased in the contralateral hemisphere. |
| (21) | Sedentary group (n = 8) Fast walk for 30 min in motorized wheels (n = 12) Fast walk for 60 min in motorized wheels (n = 11) Run for 30 min in motorized wheels (n = 10) 12 h voluntary run (n = 11) |
Ischemic (endothelin-1) |
4 days | Sprague-Dawley Rats | ELISA | Systemic: — — Central: ipsilateral/ contralateral hippocampus and córtex |
Motorized running wheel: from 4 m/min for 5 min to a walking pace of 9 m/min for 20 min over 7 days. Voluntary running: began at 5 min progressing to 60 min over 7 days. |
— — — — — – | 2 weeks post-intervention | BDNF levels were enhanced by both the ischemia and either a single 30 min walk or 12 h voluntary run. |
| (22) | Sedentary (n = 10) Motorized running wheels: 0 min (n = 10) 30 min (n = 6) 60 min (n = 6) 120 min (n = 5) Voluntary running wheels: 0 min (n = 10) 30 min (n = 6) 60 min (n = 6) 120 min (n = 5) |
Ischemic (endothelin-1) | 4 days | Sprague-Dawley Rats | ELISA | Systemic: — — Central: Ipsilateral/ contralateral hippocampus and córtex |
Voluntary running wheel: progressed from 5 to 60 min over 7 days. Motorized running wheel: progressed from 4 m/min for 5 min to 9 m/min for 20 min over 7 days. |
— — — — — – | 2 weeks post-intervention | BDNF increased after both motorized and voluntary training. However, after motorized training, a peak was not maintained over time. After voluntary training, BDNF increasing was maintained for a longer time. |
| (23) | Involuntary exercise (I-Ex, n = 14) Voluntary wheel exercise group (V-Ex, n = 14) Forced treadmill exercise group (F-Ex, n = 15) Control group (Con, n = 14) |
Ischemic Middle Cerebral Artery Occlusion | 24 hours | Sprague-Dawley Rats | ELISA | Systemic: — – Central: ipsilateral striatum and motor cortex, and hippocampus |
V-Ex rats: 23 h voluntary wheel running for 7 days F-Ex rats: motor-driven treadmill at a speed of 20 m/min with a slope of 0° for a total of 30 min every day, for 7 days I-Ex: 30 minutes FES every day, for 7 days |
De Ryck's behavioral Test | Behavioral test: daily during the 7-day intervention period (I1–I7) and repeated for three times after everyday intervention BDNF: post-intervention |
After training, Vex had significant higher behavioral test score than I-Ex, F-Ex, and Con. Both V-Ex and I-Ex had higher hippocampal BDNF concentration than F-Ex and Con. Besides, I-Ex had significantly higher striatal and cortical BDNF concentrations than F-Ex and Con |
| (24) | Control group (n = 17) Exercise Treadmill Group (n = 17) |
Hemorrhagic (heparinate bacterial collagenase) |
7–14 days | C57/BL6 Rats | Immunohistochemistry | Systemic: — — Central: both hemispheres |
Treadmill running: Intensity: from 40 m/min per 5 min to 80 m/min per 10 min for 10 days |
— — — — — – | 7 and 14 days post-intervention | BDNF-TrKB was increased 7 days post-training for both groups and returned to initial levels in control 14 days post-injury |
| (25) | Total = 32 SED control SED stroke EX control Ex stroke |
Ischemic (phototrombotic) | 14 days | Wistar rats | ELISA Western Blotting Immunohistochemistry |
Systemic: — — Central: ipsilateral hippocampus, striatum and cortical area |
Treadmill training: 0.3 m/s for 30 minutes by 7 days |
— | Stroke: 15 days post-intervention Control: 7 days post-intervention |
Cortex was the most responsive area after exercise. Exercise resulted in a comparable increase in the production of mature BDNF in intact and stroke rats but increased proBDNF levels only in intact rats |
| (15) | MCAO group (n = 12) MCAO+Ex group (n = 13) |
Transient Middle Cerebral Artery Occlusion (30 min) | 5 days post stroke | Sprague-Dawley Rats | Western Blotting | Systemic: — — Central: ipsilateral cortex and striatum |
Treadmill training 30 min 5 days per week Duration: 5th-28th day post-stroke |
Rotarod (behavioral test) | Behavioral test: 3, 7, 14, 21, 28, 35, 42, 49, 56, and 63 days post stroke BDNF: 91 days post-stroke (63 days after the end of training) |
Exercise improved functional recovery and increased BDNF levels in cortex and striatum. |
| (16) | sed VO (n = 6) sed sham (n = 6) trained VO (n = 6) trained sham (n = 6) |
Left Common Carotid Artery Occlusion | 1–7 days | Wistar rats | Western Blotting | Systemic: — — Central: ipsilateral and contralateral motor areas |
Treadmill training (7 days, 30 min/day, 18 m/min): | — — — — — – | BDNF: post-intervention | Treadmill training increased BDNF levels in the contralateral hemisphere. |
| (19) | Control group (n = 15) Study group (n = 15) |
Ischemic | 3–18 months | Human | ELISA | Systemic: serum Central: — — |
G1: Conventional physical therapy (Stretching, facilitation for weak muscles, strengthening, posture control, balance, gait and functional training) G2: Conventional physical therapy + Bicycle ergometer (40–45 min) Protocol: 3 times/week by 3 weeks |
— — — — — – | Pre and post 8 weeks training | G2 showed higher BDNF levels compared to G1 post-training. There were correlation between BDNF concentration and cognitive function post-training. |
| (26) | pMCAO group (n = 20), pMCAO + Ex group (n = 15) sham-operated group (n = 20) |
Right Middle Cerebral Artery Occlusion | 3–19 days | Sprague-Dawley Rats | Western Blotting | Systemic: — — Central: brain tissue |
Treadmill training: 10 m/min for 20 min per day in the first 2 days, then 15 m/min for 30 min per day in the following 14 days |
mNSS | Neurological Function: 24 h, on day 3, 8, 12 and 19 after lesion BDNF: post-surgery and intervention |
The mNSS in pMCAO + Ex group was lower than that in pMCAO group on day 19 post-MCAO. The protein expressions levels of BDNF was downregulated after cerebral ischemia and upregulated after treadmill exercise. |
| (27) | sham-operation group (n = 10) sham-operation + exercise group (n = 10) ischemia-induction group (n = 10) ischemia-induction + exercise group (n = 10) |
Common Carotid Arteries Occlusion | 1 day and 2 weeks | Gerbil | Western Blotting | Systemic: — — Central: Hippocampus |
Treadmill training: 30 min, once a day for 2 weeks, at a speed of 2 m/min for the first 5 min, 5 m/min for the following 5 min, and 8 m/min for the last 20 min | — — — — — – | BDNF: post-surgery and intervention | BDNF expression was increased by the induction of ischemia, while treadmill exercise further increased BDNF expression in the ischemic gerbils. |
| (28) | Control Group (n = 15) Low Training (n = 15) Gradually Increasing (n = 15) High Training (n = 15) |
Middle Cerebral Artery Occlusion | 1–7 days | Sprague-Dawley | ELISA | Systemic: — – Central: hippocampus, striatum, and sensorimotor cortex |
Treadmill training: for 7 days Low Training - 30 min with a 10-min rest between 10 min of running section at a velocity of 5 m/min High Training: at 26 m/min with the same training and rest regimens Gradually Training: from 5 m/min on the 1st day (D1) up to 26 m/min on the last day (D7) |
Longa's test De Ryck behavioral test |
Behavioral Tests: 24 h post-lesion, and daily BDNF: pre training, 2 h after last training session (8 days post-stroke) |
Hippocampal BDNF concentrations were significantly higher than in both the striatum and cortex for all groups. Gradually intensity rats showed the highest BDNF levels in the hippocampus and striatum. BDNF levels in Low Intensity and High Intensity rats were significantly higher in the hippocampus and striatum than control rats. |
| (29) | Sham group (n = 14) Ischemia group (n = 7) Sedentary group (SD4, n = 14) One week treadmill (TR1, n = 14) Four weeks treadmill (TR4, n = 14) |
Common carotid arteries occlusion | 5 days - 4 weeks post-stroke | Mongolian gerbils | Immunohistochemistry Western Blotting |
Systemic: — — Central: hippocampus, CA1 region and dentate gyrus |
Treadmill training: 30 min/day, 5 days/week for 1 (TR1) or 4 (TR4) consecutive weeks, at speed of 5 m/min for the first 5 min, 7 m/min for the next 5 min, and 10 m/min for the last 20 min with 0° inclination. | — — — — — – | BDNF: 5 days after injury, 1 and 4 weeks from 5 days post-ischemia. | No BDNF immunoreactivity was observed in sham group; For SD4 group, it was strong expressed in CA1 and DG. For TR4, the density of BDNF of CA1 region is similar to the SD4 groups, and higher in the DG compared with SD4. Regarding to protein levels (CA1 and DG), all groups presented higher values compared to sham, SD4 showed higher lower levels only in DG compared to TR groups, and TR4 had higher levels only DG compared to TR1. For protein levels in hippocampus, TR groups presented higher levels compared to sham group, and TR4 groups also showed higher levels compared to SD4. |
| (30) | Sham group (n = 7) Non-exercise group (NE, n = 12) Early exercise group (Early, n = 7) Late exercise group (Later, n = 7) |
Right external carotid artery occlusion with injection polystyrene into common carotid artery | 1–22 days | Sprague-Dawley Rats | ELISA | Systemic: — — Central: right hippocampus |
Treadmill training: 15 m/min for 30 min every day during 1 week. | — — — — — – | BDNF: before injection, at 1, 8, 15, and 22 day after injection | Compared to the moment before injection, the early and late groups presented higher BDNF levels at 7 and 15 days, respectively. |
| (31) | Sham control (SC, n = 11) Sham exercise (SE, n = 11) ICH control (IC, n = 14) ICH exercise (IE, n = 14) |
Hemorrhagic (collagenase type IV) | 1–15 days | Wistar rats | Western Blotting | Systemic: — — Central: ipsilateral and contralateral motor cortex |
Treadmill training: 30 minutes, once a day for 11 consecutive days (from day 4 to day 14 after injury), at a speed of 9 m/min | Motor deficit score, Beam-walking test Cylinder test |
Behavioral Tests: 1, 3, 7, 10, and 15 days after injury (motor deficit and beam-walking test) and 1 day prior surgery an at 3, 7, and 15 days after surgery (cylinder test) BDNF: at 15 days after injury |
Motor function of exercise group with injury (IE) improved in all behavior tests compared with exercise control group (IC). TrkB expression levels increased in IE group compared to IC, however, no differences in BDNF expression levels was found between groups. |
| FUNCTIONAL TRAINING | ||||||||||
| (18) | Control Stroke (n = 11) Control Sham (n = 12) FUMT Stroke (n = 11) FUMT Sham (n = 11) |
Ischemic (endothelin-1) | 1–21 days | Sprague-Dawley Rats | Immunohistochemistry | Systemic: — — Central: both hemispheres |
CIMT during 30 min daily | TFP, VFP, forelimb postural reflex test, Schallert cylinder test, Horizontal ladder test | 1, 3, 6, 10, 14, 18, and 21 days post-injury | CIMT accelerated the functional recovery of the limb when compared to the control, but did not affect the expression of BDNF in the hemisphere ipsilateral to the lesion. |
| (32) | Total = 20 Control group (CON): 1 week post-stroke (CON1) 4 weeks post-stroke (CON4) Experimental group (SRT - skilled reach training) 1 week post-stroke (SRT1) 4 weeks post-stroke (SRT4) |
Hemorrhagic (collagenase type VII) | 1 and 4 weeks | Sprague-Dawley Rats | Western Blotting | Systemic: — — Central: brain tissue |
Skilled reach training (plexiglass chamber) 15 min 6 days/week for 1 or 4 weeks |
Skilled ladder rung walking test | 1 and 4 weeks post-training | BDNF expression increased after 4 weeks of training comparing to pre-training and control group. Functional task also improved on 4 weeks experimental group, with better performance compared to control group. |
| (17) | Hemorrhage and non-treated group (ICH group: n = 9) Early-CIMT group (E-CIMT, n = 8) Late-CIMT group (L-CIMT, n = 6) Sham-operated group (sham-group, n = 6) |
Hemorrhagic (collagenase type IV) | 8–28 days | Wistar rats | Immunohistochemistry Gene expression (PCR) |
Systemic: — — Central: ipsilateral and contralateral sensorimotor cortex |
Forcing rats to use the affected forelimb in all daily activities for 7 days starting either 1 day (early CIMT) or 17 days (late CIMT) after the lesion. | Skilled reaching test Horizontal ladder stepping test |
Behavioral Tests: 10–12 and 26–28 after the lesion (reaching) and on days 12 and 28 after the lesion (ladder) BDNF: after early CIMT (day 8) and later CIMT (day 24). |
Early-CIMT improved reaching and stepping function of impaired forelimb after injury, but late-CIMT did not. Early-CIMT induced an increase in ipsilesional levels of BNDF, however, did not change levels in contralesional. Later-CIMT failed to induce changes in the BDNF levels. |
| (33) | Sham-operated (Sham, D14: n = 6, D29: n = 6) No treatment (ICH, D14: n = 6, D29: n = 7) ICH + Acrobatic Training (ICH+AT, D14: n = 6, D29: n = 6) |
Hemorrhagic (collagenase type IV) | 1–28 days | Wistar rats | Gene expression (PCR) | Systemic: — — Central: somatosensory cortex |
Each of the 5 acrobatic tasks (rope ladder, grating platform, rope, parallel bar, barrier) was performed spontaneously with 4 trials each day 4–28 days after surgery. | Forepaw Grasping, Modified Forelimb Placing, Postural Instability Test | Behavioral Tests: at day 1, 3, 7, 14, 12, and 28 after surgery. BDNF: At 14 and 29 days after surgery. |
Motor skills training after ICH enhanced the forelimb sensorimotor function. At 14 days after surgery, the BDNF mRNA expression level was downregulated in the ipsilesional cortex by ICH, and it was not upregulated by acrobatic training. At 29 days, the ICH+AT group had higher mRNA expression levels of BDNF in the ipsilesional sensorimotor cortex than the sham group. |
| AEROBIC EXERCISE + FUNCTIONAL TRAINING | ||||||||||
| (34) | No rehab (n = 7) Reach (n = 7) Run (n = 7) Run/Reach (n = 8) |
Ischemic (endothelin-1) | 5 days | Sprague-Dawley Rats | Immunohistochemistry Gene expression (PCR) |
Systemic: — — Central: ipsilateral and contralateral cingulate cortices, contra- lateral primary motor cortex and contralateral sensory cortex |
Reaching training associated or not with previous aerobic training (running) Duration: 30-120 min/day Over 5 weeks |
Skilled reaching test (staircase apparatus), forelimb asymmetry test (Plexigas cylinder), Ladder rung walking test | Functional tests: 2 days prior to stroke, 3 days post-stroke and 2, 3, 4, and 5 weeks after stroke BDNF: 3 days following the last rehabilitation session |
Aerobic exercise followed by reaching training improved reaching skill. There was no group effect on expression of BDNF. |
| (35) | Total = 30 Control (CON) Skilled reach training (SC) Treadmill exercise (TE) |
Left Middle Cerebral Artery Occlusion | 2 weeks | Sprague-Dawley Rats | Western Blotting | Systemic: — — Central: brain tissue |
Skilled reach training (plexiglass chamber): 30 min 6 days/week for 2 weeks Treadmill training: not described. |
— — — — — – | BDNF: 2 weeks after surgery | BDNF expression in SC and TE groups were higher compared to CON group, however, no differences between SC and TE groups were observed. |