Mechanism by which hyperglycemia regulates precursor of brain-derived neurotrophic factor expression to exacerbate neurological injury and inflammation in a mouse model of spinal cord ischemia-reperfusion injury.
10.11817/j.issn.1672-7347.2024.240198
- Author:
Wei LUO
1
;
Xuemei MIAO
2
;
Tao LIU
2
;
Yiyu XIONG
2
;
Ruping DAI
2
;
Hui LI
3
Author Information
1. Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha 410011, China. luoweianes@csu.edu.cn.
2. Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha 410011, China.
3. Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha 410011, China. lihui_1166@csu.edu.cn.
- Publication Type:Journal Article
- Keywords:
diabetes mellitus;
hyperglycemia;
neuroinflammation;
precursor of brain-derived neurotrophic factor;
spinal cord ischemia-reperfusion injury
- MeSH:
Animals;
Male;
Hyperglycemia/metabolism*;
Brain-Derived Neurotrophic Factor/genetics*;
Mice, Inbred C57BL;
Reperfusion Injury/metabolism*;
Mice;
Diabetes Mellitus, Experimental/metabolism*;
Inflammation/metabolism*;
Disease Models, Animal;
Spinal Cord/metabolism*;
Tumor Necrosis Factor-alpha/metabolism*;
Protein Precursors/genetics*;
Spinal Cord Ischemia/metabolism*;
Interleukin-6/metabolism*;
Interleukin-1beta/metabolism*
- From:
Journal of Central South University(Medical Sciences)
2024;49(12):1875-1884
- CountryChina
- Language:English
-
Abstract:
OBJECTIVES:Spinal cord ischemia-reperfusion injury (SCIRI) remains a major challenge in the field of organ protection due to the lack of effective prevention and therapeutic strategies. Hyperglycemia, a common perioperative condition, contributes to neurological injury via multiple mechanisms. However, its role and underlying mechanism in SCIRI are still unclear. This study aims to investigate the involvement of the precursor of brain-derived neurotrophic factor (proBDNF) in hyperglycemia-induced SCIRI in mice.
METHODS:Eight-week-old male C57BL/6 mice were randomly assigned to a control group (Vehicle) or a diabetes mellitus (DM) group. The DM group was established using intraperitoneal injection of streptozotocin (STZ) combined with 10% sucrose water. The Vehicle group received an equal volume of 50 mmol/L sodium citrate buffer (pH 4.5). Fasting blood-glucose levels ≥11.1 mmol/L were considered successful DM modeling. Both Vehicle and DM groups underwent SCIRI modeling via descending aortic clamping, while the Sham group underwent a sham procedure without aortic occlusion. Lower limb motor function was assessed using the Basso Mouse Scale (BMS) and its subscale (sub-BMS). Locomotor activity was evaluated using an open field test. Immunohistochemistry was performed to detect changes in neuronal nuclear protein (NeuN) and proBDNF expression in spinal cord tissues. Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to measure mRNA expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). To explore the effect of proBDNF inhibition, diabetic mice were divided into groups: A DM+SCIRI+monoclonal anti-proBDNF antibody (McAb-proB) group received an intraperitoneal injection of 100 μg of McAb-proB 30 minutes before SCIRI modeling, and a DM+SCIRI+Vehicle group received an equal amount of isotype immunoglobulin G. BMS and sub-BMS scores were recorded, and the gene expression of inflammatory cytokines mentioned above were evaluated.
RESULTS:Compared with the Vehicle+SCIRI group, the DM+SCIRI group showed significantly reduced BMS and sub-BMS scores, decreased NeuN expression, shorter total movement distance, slower locomotion, increased proBDNF expression, and elevated IL-1β, IL-6, and TNF-α mRNA levels (all P<0.05 or P<0.01). Compared with the DM+SCIRI+Vehicle group, the DM+SCIRI+McAb-proB group exhibited significantly improved BMS and sub-BMS scores and decreased mRNA expression of IL-1β, IL-6, and TNF-α (all P<0.05 or P<0.01).
CONCLUSIONS:Hyperglycemia exacerbates neural injury and inflammatory response in SCIRI through upregulation of proBDNF expression, delaying motor functional recovery. Antagonizing proBDNF expression can alleviate neurological damage and promote functional recovery in diabetic mice after SCIRI.
