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. 2022 Jul 19:13:925696.
doi: 10.3389/fneur.2022.925696. eCollection 2022.

Neurological recovery and antioxidant effect of erythropoietin for spinal cord injury: A systematic review and meta-analysis

Ya-Yun Zhang  1 , Min Yao  2 , Ke Zhu  2 , Rui-Rui Xue  1 , Jin-Hai Xu  1 , Xue-Jun Cui  2 , Wen Mo  1
Affiliations

Neurological recovery and antioxidant effect of erythropoietin for spinal cord injury: A systematic review and meta-analysis

Ya-Yun Zhang et al. Front Neurol. .

Abstract

Background: To critically evaluate the neurological recovery effects and antioxidant effects of erythropoietin (EPO) in rat models of spinal cord injury (SCI).

Methods: The PubMed, EMBASE, MEDLINE, ScienceDirect, and Web of Science were searched for animal experiments applying EPO to treat SCI to January 2022. We included studies which examined neurological function by the Basso, Beattie, and Bresnahan (BBB) scale, as well as cavity area and spared area, and determining the molecular-biological analysis of antioxidative effects by malondialdehyde (MDA) levels in spinal cord tissues. Meta-analysis were performed with Review Manager 5.4 software.

Results: A total of 33 studies were included in this review. The results of the meta-analysis showed that SCI rats receiving EPO therapy showed a significant locomotor function recovery after 14 days compared with control, then the superiority of EPO therapy maintained to 28 days from BBB scale. Compared with the control group, the cavity area was reduced [4 studies, weighted mean difference (WMD) = -16.65, 95% CI (-30.74 to -2.55), P = 0.02] and spared area was increased [3 studies, WMD =11.53, 95% CI (1.34 to 21.72), P = 0.03] by EPO. Meanwhile, MDA levels [2 studies, WMD = -0.63 (-1.09 to -0.18), P = 0.007] were improved in the EPO treatment group compared with control, which indicated its antioxidant effect. The subgroup analysis recommended 5,000 UI/kg is the most effective dose [WMD = 4.05 (2.23, 5.88), P < 0.0001], although its effect was not statistically different from that of 1,000 UI/kg. Meanwhile, the different rat strains (Sprague-Dawley vs. Wistar), and models of animals, as well as administration method (single or multiple administration) of EPO did not affect the neuroprotective effect of EPO for SCI.

Conclusions: This systematic review indicated that EPO can promote the recovery of the locomotor function of SCI rats. The mechanism exploration of EPO needs to be verified by experiments, and then carefully designed randomized controlled trials are needed to explore its neural recovery effects.

Keywords: antioxidant; erythropoietin; meta-analysis; neurological recovery; spinal cord injury.

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Figures

Figure 1
Figure 1
PRISMA 2009 Flow diagram.
Figure 2
Figure 2
Evolution of the scores on the BBB of the two groups including the six (1, 3, 7, 14, 21, and 28 days) evolution periods. BBB, Basso-Beattie-Bresnahan locomotor rating.
Figure 3
Figure 3
Forest plot for the effects of EPO intervention on cavity area in rats with SCI. EPO, erythropoietin; SCI, spinal cord injury.
Figure 4
Figure 4
Forest plot for the effects of EPO intervention on spared area in rats with SCI. EPO, erythropoietin; SCI, spinal cord injury.
Figure 5
Figure 5
Forest plot for the effects of EPO intervention on MDA in rats with SCI. EPO, erythropoietin; MDA, malondialdehyde.
Figure 6
Figure 6
Funnel plots of publication bias for BBB score. BBB, Basso-Beattie-Bresnahan locomotor rating.
Figure 7
Figure 7
Mechanism diagram of EPO pathway. EPO, erythropoietin; EPOR, erythropoietin receptor; Nrf2, nuclear factor 2; GSK3β, glycogen synthase kinase 3 beta; NQO1, (NAD(P)H quinone dehydrogenase 1; CHOP, C/Ebp-homologous protein; BAX, Bcl2-associated x protein; JAK2, janus activated kinase 2; FAK1, focal adhesion kinase 1; SYK, spleen tyrosine kinase; PI3K, phosphatidylinositol 3-kinase; AKT, AKT serine/threonine kinase.
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