Weight drop models of traumatic brain injuryin rats associated with cognitive disorders and glial scar formation: a systematic review
DOI:
https://doi.org/10.2478/AMB-2025-0065Keywords:
weight drop, traumatic brain injury, cognitive disorder, gliosis, ratsAbstract
Objective: Traumatic brain injury (TBI) causes persistent cognitive disorders due to glial scar formation, inhibiting axonal regeneration. Targeting glial scar formation may improve TBI-related cognitive disorders, and require standardized animal models for research. This review aims to identify a weight drop model inducing cognitive disorders and glial scar formation in rats with TBI, supporting further investigations. Methods: A literature search using PubMed, Science Direct, and ProQuest databases identified relevant articles. Inclusion criteria were randomized controlled trials published in English, in full text, between 2012 and 2022. Review articles and abstracts were excluded. Keywords were chosen via the P.I.C.O framework, and article quality was assessed using the Systematic Review Center for Laboratory Animal Experimentation guideline by three reviewers. Results: Among 1,042 articles, 32 studies demonstrated cognitive disorders in rats using the weight drop model. Three studies explored glial scar formation and found that two weight drop methods were associated with cognitive disorders and glial scar formation in rats with TBI: applying a 10-gram load from a 5 cm height to the exposed heads of Sprague–Dawley rats or using a 200 gram weight from a 2.5 cm height to the exposed skulls of mice. Conclusion: Two weight drop model methods were found to induce the formation of glial scar, which consequently resulted in persistent cognitive disorders. These discoveries provide significant insights for future research on potential interventions aimed at preventing glial scar formation and improving cognitive disturbances in TBI. Clinically, this research holds significant promise for informing treatment strategies in TBI patients by identifying targets to prevent or reverse glial scar formation. Such interventions could reduce cognitive decline, improve rehabilitation outcomes, and support the restoration of brain function. Early therapeutic approaches targeting glial scars may enable timely and effective strategies to minimize permanent neurological damage and enhance recovery in TBI patients.
References
Cortes D, Pera MF. The genetic basis of inter-individual variation in recovery from traumatic brain injury. NPJ Regen Med 2021;6(1):1-9. doi:10.1038/s41536-020-00114-y
Zhou Y, Shao A, Yao Y, et al. Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury. Cell Communication and Signaling 2020;18(1). doi:10.1186/s12964-020-00549-2
Muccigrosso MM, Ford J, Benner B, et al. Cognitive deficits develop 1 month after diffuse brain injury and are exaggerated by microglia-associated reactivity to peripheral immune challenge. Brain Behav Immun 2016;54:95-109. doi:10.1016/j.bbi.2016.01.009
Andelic N, Howe EI, Hellstrøm T, et al. Disability and quality of life 20 years after traumatic brain injury. Brain Behav 2018;8(7). doi:10.1002/brb3.1018
Ng SY, Lee AYW. Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets. Front Cell Neurosci 2019;13. doi:10.3389/fncel.2019.00528
Leibinger M, Andreadaki A, Diekmann H, Fischer D. Neuronal STAT3 activation is essential for CNTF- and inflammatory stimulation-induced CNS axon regeneration. Cell Death Dis 2013;4(9). doi:10.1038/cddis.2013.310
Ma X, Aravind A, Pfister BJ, et al. Animal Models of Traumatic Brain Injury and Assessment of Injury Severity. Mol Neurobiol 2019;56(8):5332-5345. doi:10.1007/s12035-018-1454-5
Bodnar CN, Roberts KN, Higgins EK, Bachstetter AD. A Systematic Review of Closed Head Injury Models of Mild Traumatic Brain Injury in Mice and Rats. J Neurotrauma 2019;36(11):1683-1706. doi:10.1089/neu.2018.6127
Chakraborty N, Hammamieh R, Gautam A, et al. TBI weight-drop model with variable impact heights differentially perturbs hippocampus-cerebellum specific transcriptomic profile. Exp Neurol 2021;335. doi:10.1016/j.expneurol.2020.113516
Kuo CW, Chang MY, Liu HH, et al. Cortical Electrical Stimulation Ameliorates Traumatic Brain Injury-Induced Sensorimotor and Cognitive Deficits in Rats. Front Neural Circuits 2021;15. doi:10.3389/fncir.2021.693073
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. International Journal of Surgery 2021:88;105906
Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017 Sep 21;358:j4008.
Hooijmans CR, Rovers MM, De Vries RBM, et al. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 2014;14(1). doi:10.1186/1471-2288-14-43
Shishido H, Ueno M, Sato K, et al. Traumatic brain injury by weight-drop method causes transient amyloid-β deposition and acute cognitive deficits in mice. Behavioural Neurology 2019;2019. doi:10.1155/2019/3248519
Yu Z, Xin Y, Xinran H, et al. Extracellular signal-regulated kinase-dependent phosphorylation of histone H3 serine 10 is involved in the pathogenesis of traumatic brain injury. Frontiers in Molecular Neuroscience 2022:1-26.
Tian L, Guo R, Yue X, et al. Intranasal administration of nerve growth factor ameliorate β-amyloid deposition after traumatic brain injury in rats. Brain Res 2012; 1440:47-55. doi:10.1016/j.brainres.2011.12.059
Cheng T, Yang B, Li D, et al. Wharton’s Jelly Transplantation Improves Neurologic Function in a Rat Model of Traumatic Brain Injury. Cell Mol Neurobiol 2015;35(5):641-649. doi:10.1007/s10571-015-0159-9
Chen H, Chan YL, Nguyen LT, et al. Moderate traumatic brain injury is linked to acute behaviour deficits and long term mitochondrial alterations. Clin Exp Pharmacol Physiol 2016;43(11):1107-1114. doi:10.1111/1440-1681.12650
Luo M ling, Pan L, Wang L, et al. Transplantation of NSCs Promotes the Recovery of Cognitive Functions by Regulating Neurotransmitters in Rats with Traumatic Brain Injury. Neurochem Res 2019;44(12):2765-2775. doi:10.1007/s11064-019-02897-z
Xu P, Huang X, Niu W, et al. Metabotropic glutamate receptor 5 upregulation of γ-aminobutyric acid transporter 3 expression ameliorates cognitive impairment after traumatic brain injury in mice. Brain Res Bull 2022;183:104-115. doi:10.1016/j.brainresbull.2022.03.005
Schreiber S, Lin R, Haim L, et al. Enriched environment improves the cognitive effects from traumatic brain injury in mice. Behavioural Brain Research 2014; 271:59-64. doi:10.1016/j.bbr.2014.05.060
Stetter C, Lopez-Caperuchipi S, Hopp-Krämer S, et al. Amelioration of cognitive and behavioral deficits after traumatic brain injury in coagulation factor xii deficient mice. Int J Mol Sci 2021;22(9). doi:10.3390/ijms22094855
Shavit-Stein E, Gerasimov A, Aharoni S, et al. Unexpected role of stress as a possible resilience mechanism upon mild traumatic brain injury (mTBI) in mice. Molecular and Cellular Neuroscience 2021;111. doi:10.1016/j.mcn.2020.103586
Heim LR, Bader M, Edut S, et al. The Invisibility of Mild Traumatic Brain Injury: Impaired Cognitive Performance as a Silent Symptom. J Neurotrauma 2017;34(17):2518-2528. doi:10.1089/neu.2016.4909
Li D, Ma S, Guo D, et al. Environmental Circadian Disruption Worsens Neurologic Impairment and Inhibits Hippocampal Neurogenesis in Adult Rats After Traumatic Brain Injury. Cell Mol Neurobiol 2016;36(7):1045-1055. doi:10.1007/s10571-015-0295-2
Lesniak A, Pick CG, Misicka A, et al. Biphalin protects against cognitive deficits in a mouse model of mild traumatic brain injury (mTBI). Neuropharmacology 2016;101:506-518. doi:10.1016/j.neuropharm.2015.10.014
Sofroniew MV, Vinters HV. Astrocytes: Biology and pathology. Acta Neuropathol 2010;119(1):7-35. doi:10.1007/s00401-009-0619-8
Liu S, Shen GY, Deng SK, et al. Hyperbaric oxygen therapy improves cognitive functioning after brain injury. Neural Regen Res 2013;8(35):3334-3343. doi:10.3969/j.issn.1673-5374.2013.35.008
Rachmany L, Tweedie D, Rubovitch V, et al. Cognitive impairments accompanying rodent mild traumatic brain injury involve p53-dependent neuronal cell death and are ameliorated by the tetrahydrobenzothiazole PFT-α. PLoS One 2013;8(11). doi:10.1371/journal.pone.0079837
Yang SH, Gustafson J, Gangidine M, et al. A murine model of mild traumatic brain injury exhibiting cognitive and motor deficits. Journal of Surgical Research 2013;184(2):981-988. doi:10.1016/j.jss.2013.03.075
Eakin K, Baratz-Goldstein R, Pick CG, et al. Efficacy of N-acetyl cysteine in traumatic brain injury. PLoS One 2014;9(4). doi:10.1371/journal.pone.0090617
Edut S, Rubovitch V, Rehavi M, et al. A Study on the Mechanism by Which MDMA Protects Against Dopaminergic Dysfunction After Minimal Traumatic Brain Injury (mTBI) in Mice. Journal of Molecular Neuroscience 2014;54(4):684-697. doi:10.1007/s12031-014-0399-z
Si D, Yang P, Jiang R, et al. Improved cognitive outcome after progesterone administration is associated with protecting hippocampal neurons from secondary damage studied in vitro and in vivo. Behavioural Brain Research 2014; 264:135-142. doi:10.1016/j.bbr.2014.01.049
Baratz R, Tweedie D, Wang JY, et al. Transiently lowering tumor necrosis factor-aα synthesis ameliorates neuronal cell loss and cognitive impairments induced by minimal traumatic brain injury in mice. J Neuroinflammation 2015;12(1). doi:10.1186/s12974-015-0237-4
Baratz-Goldstein R, Deselms H, Heim LR, et al. Thioredoxin-mimetic-peptides protect cognitive function after mild traumatic brain injury (mTBI). PLoS One 2016;11(6). doi:10.1371/journal.pone.0157064
Ji X, Peng D, Zhang Y, et al. Astaxanthin improves cognitive performance in mice following mild traumatic brain injury. Brain Res 2017; 1659:88-95. doi:10.1016/j.brainres.2016.12.031
Khandelwal VKM, Singh P, Ravingerova T, et al. Comparison of different osmotic therapies in a mouse model of traumatic brain injury. Pharmacological Reports 2017;69(1):176-184. doi:10.1016/j.pharep.2016.10.007
Shishido H, Kishimoto Y, Kawai N, et al. Traumatic brain injury accelerates amyloid-β deposition and impairs spatial learning in the triple-transgenic mouse model of Alzheimer’s disease. Neurosci Lett 2016; 629:62-67. doi:10.1016/j.neulet.2016.06.066
Benady A, Freidin D, Pick CG, Rubovitch V. GM1 ganglioside prevents axonal regeneration inhibition and cognitive deficits in a mouse model of traumatic brain injury. Sci Rep 2018;8(1). doi:10.1038/s41598-018-31623-y
Bader M, Li Y, Tweedie D, et al. Neuroprotective Effects and Treatment Potential of Incretin Mimetics in a Murine Model of Mild Traumatic Brain Injury. Front Cell Dev Biol 2020;7. doi:10.3389/fcell.2019.00356
Lecca D, Bader M, Tweedie D, et al. (-)-Phenserine and the prevention of pre-programmed cell death and neuroinflammation in mild traumatic brain injury and Alzheimer’s disease challenged mice. Neurobiol Dis 2019;130. doi:10.1016/j.nbd.2019.104528
Ahmed ME, Selvakumar GP, Kempuraj D, et al. Glia Maturation Factor (GMF) Regulates Microglial Expression Phenotypes and the Associated Neurological Deficits in a Mouse Model of Traumatic Brain Injury. Mol Neurobiol 2020;57(11):4438-4450. doi:10.1007/s12035-020-02040-y
Farr SA, Cuzzocrea S, Esposito E, et al. Adenosine A3 receptor as a novel therapeutic target to reduce secondary events and improve neurocognitive functions following traumatic brain injury. J Neuroinflammation 2020;17(1). doi:10.1186/s12974-020-02009-7
Kempuraj D, Ahmed ME, Selvakumar GP, et al. Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury. Mediators Inflamm 2020;2020. doi:10.1155/2020/4243953
Sekar S, Viswas RS, Mahabadi HM, et al. Concussion/mild traumatic brain injury (Tbi) induces brain insulin resistance: a positron emission tomography (pet) scanning study. Int J Mol Sci 2021;22(16). doi:10.3390/ijms22169005
Qubty D, Frid K, Har-Even M, et al. Nano-PSO Administration Attenuates Cognitive and Neuronal Deficits Resulting from Traumatic Brain Injury. Molecules 2022;27(9). doi:10.3390/molecules27092725
Downloads
Published
Issue
Section
License
Copyright (c) 2025 D. Wardhana, H. Khotimah, T. Nazwar, Nurdiana (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
You are free to share, copy and redistribute the material in any medium or format under these terms.
Journal Acta Medica Bulgarica 
