Effects of α1-antitrypsin on motor function in mice with immature brain white matter injury
LI Wen-Dong, SONG Juan, ZHANG Han, YANG Lu-Xiang, YUE Yu-Yang, ZHANG Xin-Ling, WANG Yong
Department of Pediatrics, Third Affiliated Hospital of Zhengzhou University/Henan Key Laboratory of Child Brain Injury, Zhengzhou 450052, China (Song J, Email: songjuanzzu@163.com)
Abstract Objective To investigate the effects of α1-antitrypsin (AAT) on motor function in adult mice with immature brain white matter injury. Methods Five-day-old C57BL/6J mice were randomly assigned to the sham surgery group (n=27), hypoxia-ischemia (HI) + saline group (n=27), and HI+AAT group (n=27). The HI white matter injury mouse model was established using HI methods. The HI+AAT group received intraperitoneal injections of AAT (50 mg/kg) 24 hours before HI, immediately after HI, and 72 hours after HI; the HI+saline group received intraperitoneal injections of the same volume of saline at the corresponding time points. Brain T2-weighted magnetic resonance imaging scans were performed at 7 and 55 days after modeling. At 2 months of age, adult mice were evaluated for static, dynamic, and coordination parameters using the Catwalk gait analysis system. Results Compared to the sham surgery group, mice with HI injury showed high signal intensity on brain T2-weighted magnetic resonance imaging at 7 days after modeling, indicating significant white matter injury. The white matter injury persisted at 55 days after modeling. In comparison to the sham surgery group, the HI+saline group exhibited decreased paw print area, maximum contact area, average pressure, maximum pressure, paw print width, average velocity, body velocity, stride length, swing speed, percentage of gait pattern AA, and percentage of inter-limb coordination (left hind paw → left front paw) (P<0.05). The HI+saline group showed increased inter-paw distance, percentage of gait pattern AB, and percentage of phase lag (left front paw → left hind paw) compared to the sham surgery group (P<0.05). In comparison to the HI+saline group, the HI+AAT group showed increased average velocity, body velocity, stride length, and swing speed (right front paw) (P<0.05). Conclusions The mice with immature brain white matter injury may exhibit significant motor dysfunction in adulthood, while the use of AAT can improve some aspects of their motor function.
LI Wen-Dong,SONG Juan,ZHANG Han et al. Effects of α1-antitrypsin on motor function in mice with immature brain white matter injury[J]. CJCP, 2024, 26(2): 181-187.
LI Wen-Dong,SONG Juan,ZHANG Han et al. Effects of α1-antitrypsin on motor function in mice with immature brain white matter injury[J]. CJCP, 2024, 26(2): 181-187.
Ohuma EO, Moller AB, Bradley E, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis[J]. Lancet, 2023, 402(10409): 1261-1271. PMID: 37805217. DOI: 10.1016/S0140-6736(23)00878-4.
de Serres F, Blanco I. Role of alpha-1 antitrypsin in human health and disease[J]. J Intern Med, 2014, 276(4): 311-335. PMID: 24661570. DOI: 10.1111/joim.12239.
Timotius IK, Roelofs RF, Richmond-Hacham B, et al. CatWalk XT gait parameters: a review of reported parameters in pre-clinical studies of multiple central nervous system and peripheral nervous system disease models[J]. Front Behav Neurosci, 2023, 17: 1147784. PMID: 37351154. PMCID: PMC10284348. DOI: 10.3389/fnbeh.2023.1147784.
Vannucci SJ, Back SA. The Vannucci model of hypoxic-ischemic injury in the neonatal rodent: 40 years later[J]. Dev Neurosci, 2022, 44(4-5): 186-193. PMID: 35263745. DOI: 10.1159/000523990.
Borjini N, Sivilia S, Giuliani A, et al. Potential biomarkers for neuroinflammation and neurodegeneration at short and long term after neonatal hypoxic-ischemic insult in rat[J]. J Neuroinflammation, 2019, 16(1): 194. PMID: 31660990. PMCID: PMC6819609. DOI: 10.1186/s12974-019-1595-0.
Caeyenberghs K, Leemans A, Geurts M, et al. Correlations between white matter integrity and motor function in traumatic brain injury patients[J]. Neurorehabil Neural Repair, 2011, 25(6): 492-502. PMID: 21427274. DOI: 10.1177/1545968310394870.
Shao R, Sun D, Hu Y, et al. White matter injury in the neonatal hypoxic-ischemic brain and potential therapies targeting microglia[J]. J Neurosci Res, 2021, 99(4): 991-1008. PMID: 33416205. DOI: 10.1002/jnr.24761.
Timotius IK, Bieler L, Couillard-Despres S, et al. Combination of defined CatWalk gait parameters for predictive locomotion recovery in experimental spinal cord injury rat models[J]. eNeuro, 2021, 8(2): ENEURO.0497-20.2021. PMID: 33593735. PMCID: PMC7986542. DOI: 10.1523/ENEURO.0497-20.2021.
Pitzer C, Kurpiers B, Eltokhi A. Gait performance of adolescent mice assessed by the CatWalk XT depends on age, strain and sex and correlates with speed and body weight[J]. Sci Rep, 2021, 11(1): 21372. PMID: 34725364. PMCID: PMC8560926. DOI: 10.1038/s41598-021-00625-8.
Campos-Pires R, Onggradito H, Ujvari E, et al. Xenon treatment after severe traumatic brain injury improves locomotor outcome, reduces acute neuronal loss and enhances early beneficial neuroinflammation: a randomized, blinded, controlled animal study[J]. Crit Care, 2020, 24(1): 667. PMID: 33246487. PMCID: PMC7691958. DOI: 10.1186/s13054-020-03373-9.
Liu X, Zhang M, Liu H, et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate cerebral ischemia-reperfusion injury-induced neuroinflammation and pyroptosis by modulating microglia M1/M2 phenotypes[J]. Exp Neurol, 2021, 341: 113700. PMID: 33741350. DOI: 10.1016/j.expneurol.2021.113700.
21 Deacon RM. Measuring motor coordination in mice[J]. J Vis Exp, 2013(75): e2609. PMID: 23748408. PMCID: PMC3724562. DOI: 10.3791/2609.
Kappos EA, Sieber PK, Engels PE, et al. Validity and reliability of the CatWalk system as a static and dynamic gait analysis tool for the assessment of functional nerve recovery in small animal models[J]. Brain Behav, 2017, 7(7): e00723. PMID: 28729931. PMCID: PMC5516599. DOI: 10.1002/brb3.723.
Wang Y, Luo W, Reiser G. Trypsin and trypsin-like proteases in the brain: proteolysis and cellular functions[J]. Cell Mol Life Sci, 2008, 65(2): 237-252. PMID: 17965832. DOI: 10.1007/s00018-007-7288-3.
Zhukovsky N, Silvano M, Filloux T, et al. Alpha-1 antitrypsin reduces disease progression in a mouse model of Charcot-Marie-Tooth type 1A: a role for decreased inflammation and ADAM-17 inhibition[J]. Int J Mol Sci, 2022, 23(13): 7405. PMID: 35806409. PMCID: PMC9266995. DOI: 10.3390/ijms23137405.