Hyperbaric Oxygen Improves Functional Recovery of Rats After Spinal Cord Injury via Activating Stromal Cell-Derived Factor-1/CXC Chemokine Receptor 4 Axis and Promoting Brain-Derived Neurotrophic Factor Expression
Spinal cord injury (SCI) is a significant medical concern worldwide, leading to severe neurological deficits and substantial socioeconomic burdens. The injury progression involves two phases: primary and secondary. The primary injury results from initial mechanical damage, while the secondary injury involves a cascade of cellular and molecular events, including inflammation, edema, and hemorrhage, which hinder nerve repair and regeneration. Despite extensive research, effective treatments for SCI remain limited. Hyperbaric oxygen (HBO) therapy, which involves breathing 100% oxygen at increased atmospheric pressure, has shown promise in improving neurological recovery in both acute and chronic SCI. This study aimed to explore the mechanisms underlying HBO’s protective effects in a rat model of SCI, focusing on the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis and the expression of brain-derived neurotrophic factor (BDNF).
To investigate the effects of HBO on SCI recovery, an acute SCI model was established in Sprague-Dawley rats using the Allen method. Sixty rats were divided into four groups: sham-operated, SCI, SCI treated with HBO (SCI+HBO), and SCI treated with both HBO and AMD3100 (an antagonist of CXCR4; SCI+HBO+AMD). HBO treatment was administered twice daily for three days and then once daily for up to 28 days post-surgery. Neurological assessments were conducted using the Basso-Bettie-Bresnahan (BBB) scoring system on postoperative days (POD) 7, 14, 21, and 28. Spinal cord tissues were harvested to evaluate the expression of SDF-1, CXCR4, and BDNF at mRNA and protein levels using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, and histopathological analysis.
The results demonstrated that HBO treatment significantly improved functional recovery in SCI rats. The BBB scores in the SCI+HBO group were higher than those in the SCI group on POD 14 (1.25±0.75 vs. 1.03±0.66, P<0.05), 21 (5.27±0.89 vs. 2.56±1.24, P<0.05), and 28 (11.35±0.56 vs. 4.23±1.20, P<0.05). These findings indicate that HBO treatment enhanced locomotor function recovery in SCI rats.
At the molecular level, HBO treatment significantly increased the mRNA levels of SDF-1, CXCR4, and BDNF. On POD 21, the mRNA level of SDF-1 in the SCI+HBO group was 2.89±1.60 compared to 1.56±0.98 in the SCI+HBO+AMD group (P<0.05). The mRNA level of CXCR4 in the SCI+HBO group was higher than in the SCI group on POD 7 (2.99±1.60 vs. 1.31±0.98, P<0.05), POD 14 (4.18±1.60 vs. 0.80±0.34, P<0.05), and POD 21 (2.10±1.01 vs. 1.15±0.03, P<0.05). Similarly, the mRNA level of BDNF in the SCI+HBO group was higher than in the SCI group on POD 7 (3.04±0.41 vs. 2.75±0.31, P<0.05) and POD 14 (3.88±1.59 vs. 1.11±0.40, P<0.05). These results suggest that HBO treatment activates the SDF-1/CXCR4 axis and promotes BDNF expression, contributing to the recovery of neurological function after SCI.
Histopathological analysis further supported the beneficial effects of HBO treatment. Hematoxylin and eosin (H&E) staining revealed that the SCI+HBO group exhibited better histologic characteristics, with reduced edema, hemorrhage, and neutrophil infiltration compared to the SCI and SCI+HBO+AMD groups. Immunohistochemical staining showed that HBO treatment increased the expression of SDF-1 in white matter and BDNF in spinal cord tissues, consistent with the findings at the mRNA and protein levels.
Western blot analysis confirmed the upregulation of SDF-1, CXCR4, and BDNF proteins in the SCI+HBO group. The normalized protein expression levels of SDF-1/β-actin and CXCR4/β-actin were significantly higher in the SCI+HBO group compared to the SCI and SCI+HBO+AMD groups at various time points. The expression of BDNF was also elevated in the SCI+HBO group, indicating that HBO treatment promotes the expression of neurotrophic factors, which are crucial for neuronal survival and regeneration.
The study also explored the role of the SDF-1/CXCR4 axis in the protective effects of HBO. The administration of AMD3100, a CXCR4 antagonist, significantly inhibited the HBO-induced activation of SDF-1 and CXCR4, as evidenced by lower mRNA and protein levels in the SCI+HBO+AMD group. This inhibition also attenuated the functional recovery observed in the SCI+HBO group, further supporting the involvement of the SDF-1/CXCR4 axis in HBO’s therapeutic effects.
BDNF, a key neurotrophic factor, plays a pivotal role in synaptic plasticity, learning, and memory. The increased expression of BDNF in the SCI+HBO group suggests that HBO treatment enhances neuroplasticity and prevents neurodegeneration. BDNF’s neuroprotective effects are likely mediated through its ability to modulate the expression of CXCR4 and SDF-1, indicating a synergistic relationship between the SDF-1/CXCR4 axis and BDNF in promoting recovery after SCI.
The findings of this study provide valuable insights into the mechanisms underlying HBO’s therapeutic effects in SCI. By activating the SDF-1/CXCR4 axis and promoting BDNF expression, HBO treatment enhances functional recovery and reduces secondary injury in SCI rats. These results not only offer a potential therapeutic strategy for SCI but also lay the foundation for future research to further elucidate the molecular pathways involved in HBO’s protective effects.
In conclusion, HBO treatment significantly improves functional recovery in rats after SCI by activating the SDF-1/CXCR4 axis and promoting BDNF expression. This study highlights the potential of HBO as a safe and effective treatment for SCI, warranting further investigation into its clinical applications. The dynamic changes in the expression of SDF-1, CXCR4, and BDNF at various time points after SCI and HBO treatment provide a comprehensive understanding of the molecular mechanisms involved in HBO’s therapeutic effects.
doi.org/10.1097/CM9.0000000000000115
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