The effects of aerobic exercise on neuroimmune responses in animals with traumatic peripheral nerve injury: a systematic review with meta-analyses

Abstract

Background: Increasing pre-clinical evidence suggests that aerobic exercise positively modulates neuroimmune responses following traumatic nerve injury. However, meta-analyses on neuroimmune outcomes are currently still lacking. This study aimed to synthesize the pre-clinical literature on the effects of aerobic exercise on neuroimmune responses following peripheral nerve injury.

Methods: MEDLINE (via Pubmed), EMBASE and Web of Science were searched. Controlled experimental studies on the effect of aerobic exercise on neuroimmune responses in animals with a traumatically induced peripheral neuropathy were considered. Study selection, risk of bias assessment and data extraction were performed independently by two reviewers. Results were analyzed using random effects models and reported as standardized mean differences. Outcome measures were reported per anatomical location and per class of neuro-immune substance.

Results: The literature search resulted in 14,590 records. Forty studies were included, reporting 139 comparisons of neuroimmune responses at various anatomical locations. All studies had an unclear risk of bias. Compared to non-exercised animals, meta-analyses showed the following main differences in exercised animals: (1) in the affected nerve, tumor necrosis factor-α (TNF-α) levels were lower (p = 0.003), while insulin-like growth factor-1 (IGF-1) (p < 0.001) and Growth Associated Protein 43 (GAP43) (p = 0.01) levels were higher; (2) At the dorsal root ganglia, brain-derived neurotrophic factor (BDNF)/BDNF mRNA levels (p = 0.004) and nerve growth factor (NGF)/NGF mRNA (p < 0.05) levels were lower; (3) in the spinal cord, BDNF levels (p = 0.006) were lower; at the dorsal horn, microglia (p < 0.001) and astrocyte (p = 0.005) marker levels were lower; at the ventral horn, astrocyte marker levels (p < 0.001) were higher, and several outcomes related to synaptic stripping were favorably altered; (4) brainstem 5-HT2A receptor levels were higher (p = 0.001); (5) in muscles, BDNF levels (p < 0.001) were higher and TNF-α levels lower (p < 0.05); (6) no significant differences were found for systemic neuroimmune responses in blood or serum.

Conclusion: This review revealed widespread positive modulatory effects of aerobic exercise on neuroimmune responses following traumatic peripheral nerve injury. These changes are in line with a beneficial influence on pro-inflammatory processes and increased anti-inflammatory responses. Given the small sample sizes and the unclear risk of bias of the studies, results should be interpreted with caution.

Keywords: Cytokines; Exercise; Macrophages; Mechanisms; Neuro-immune system; Neuroinflammation; Neurotransmitters; Neurotrophins; Peripheral neuropathy; Physical activity.

Fig. 1

Flowchart of study selection

Fig. 2

Risk of bias assessment. A ‘ + ’ represents low risk of bias, a ‘−’ high risk of bias and ‘?’ unclear risk of bias

Fig. 3

Results meta-analyses. N = number of studies (number of comparisons). * p < 0.05; ^# Iba1 or CD⁻11b⁺; †GFAP; ^e Iba1; Results in favor of exercised animals compared to controls. BDNF brain-derived neurotrophic factor, GAD67 glutamic acid decarboxylase 67, GAP43 Growth Associated Protein 43, GDNF glial cell line-derived neurotrophic factor, IGF-1 insulin-like growth factor-1, IL Interleukin, NGF nerve growth factor, PNN perineuronal net, SMD standardized mean difference, TNF-α tumor necrosis factor-α, VGat1 vesicular GABA transporter 1, VGlut1 vesicular glutamate transporter 1

Fig. 3

Results meta-analyses. N = number of studies (number of comparisons). * p < 0.05; ^# Iba1 or CD⁻11b⁺; †GFAP; ^e Iba1; Results in favor of exercised animals compared to controls. BDNF brain-derived neurotrophic factor, GAD67 glutamic acid decarboxylase 67, GAP43 Growth Associated Protein 43, GDNF glial cell line-derived neurotrophic factor, IGF-1 insulin-like growth factor-1, IL Interleukin, NGF nerve growth factor, PNN perineuronal net, SMD standardized mean difference, TNF-α tumor necrosis factor-α, VGat1 vesicular GABA transporter 1, VGlut1 vesicular glutamate transporter 1