Neuroscience Program, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Department of Anatomy, Physiology, and Genetics, Uniformed Services University, Room C2099, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
J Neuroinflammation. 2017 Aug 18;14(1):161. doi: 10.1186/s12974-017-0933-3.
Spinal cord injury (SCI) among people over age 40 has been steadily increasing since the 1980s and is associated with worsened outcome than injuries in young people. Age-related increases in reactive oxygen species (ROS) are suggested to lead to chronic inflammation. The NADPH oxidase 2 (NOX2) enzyme is expressed by microglia and is a primary source of ROS. This study aimed to determine the effect of age on inflammation, oxidative damage, NOX2 gene expression, and functional performance with and without SCI in young adult (3 months) and middle-aged (12 months) male rats.
Young adult and middle-aged rats were assessed in two groups-naïve and moderate contusion SCI. Functional recovery was determined by weekly assessment with the Basso, Beattie, and Breshnahan general motor score (analyzed two-way ANOVA) and footprint analysis (analyzed by Chi-square analysis). Tissue was analyzed for markers of oxidative damage (8-OHdG, Oxyblot, and 3-NT), microglial-related inflammation (Iba1), NOX2 component (p47, p22, and gp91), and inflammatory (CD86, CD206, TNFα, and NFκB) gene expression (all analyzed by unpaired Student's t test).
In both naïve and injured aged rats, compared to young rats, tissue analysis revealed significant increases in 8-OHdG and Iba1, as well as inflammatory and NOX2 component gene expression. Further, injured aged rats showed greater lesion volume rostral and caudal to the injury epicenter. Finally, injured aged rats showed significantly reduced Basso-Beattie-Bresnahan (BBB) scores and stride length after SCI.
These results show that middle-aged rats demonstrate increased microglial activation, oxidative stress, and inflammatory gene expression, which may be related to elevated NOX2 expression, and contribute to worsened functional outcome following injury. These findings are essential to elucidating the mechanisms of age-related differences in response to SCI and developing age-appropriate therapeutics.
自 20 世纪 80 年代以来，40 岁以上人群的脊髓损伤（SCI）一直在稳步增加，且与年轻人的损伤相比，预后更差。据推测，与年龄相关的活性氧（ROS）增加会导致慢性炎症。NADPH 氧化酶 2（NOX2）酶由小胶质细胞表达，是 ROS 的主要来源。本研究旨在确定年龄对年轻成年（3 个月）和中年（12 个月）雄性大鼠 SCI 后炎症、氧化损伤、NOX2 基因表达和功能表现的影响。
将年轻成年和中年大鼠分为两组进行评估——未损伤和中度挫伤 SCI。通过每周评估 Basso、Beattie 和 Breshnahan 总体运动评分（采用双因素方差分析）和足迹分析（采用卡方分析）来确定功能恢复情况。通过 8-OHdG、Oxyblot 和 3-NT 分析氧化损伤标志物、Iba1 分析小胶质细胞相关炎症、p47、p22 和 gp91 分析 NOX2 成分、CD86、CD206、TNFα 和 NFκB 分析炎症基因表达（所有分析均采用未配对学生 t 检验）。
在未损伤和损伤的老年大鼠中，与年轻大鼠相比，组织分析显示 8-OHdG 和 Iba1 以及炎症和 NOX2 成分基因表达显著增加。此外，损伤后的老年大鼠在损伤中心的头侧和尾侧显示出更大的损伤体积。最后，损伤后的老年大鼠在 SCI 后表现出明显降低的 Basso-Beattie-Bresnahan（BBB）评分和步幅长度。
这些结果表明，中年大鼠表现出小胶质细胞激活、氧化应激和炎症基因表达增加，这可能与 NOX2 表达升高有关，并导致损伤后的功能预后恶化。这些发现对于阐明与年龄相关的 SCI 反应差异的机制以及开发适合年龄的治疗方法至关重要。
