Establishment and evaluation of a novel rat model of the fourth ventricle hemorrhage

Abstract

Background: Hemorrhagic expansion into the fourth ventricle is an independent risk factor for poor outcomes in intraventricular hemorrhage (IVH) patients. However, to date, available animal models of IVH are limited to models of supratentorial ventricular hemorrhage, and there are no specific models of fourth ventricle hemorrhage. This limitation hinders comprehensive basic research and the understanding of the pathophysiological changes that occur following fourth ventricle hemorrhage. Therefore, the development of an animal model of fourth ventricle hemorrhage is highly important.

Methods: In this study, a novel rat model of fourth ventricle hemorrhage was established via autologous blood injection through the foramen of Magendie. Anesthetized rats were positioned in a stereotaxic apparatus with their heads tilted downward at an angle of approximately 20° relative to the vertical axis. A needle was inserted through the foramen, and autologous blood obtained from the rat's heart was injected into the fourth ventricle via a microinfusion pump. Systematic evaluations of the model were conducted using small-animal magnetic resonance imaging, histopathological analysis, and neurological function assessment.

Results: The rats developed stable and reproducible fourth ventricle hematomas and ventricular dilation. They also exhibited acute-phase hydrocephalus and pathological features of perilesional brain tissue injury, with observed neurological deficits comparable to patients with fourth ventricle hemorrhage.

Conclusion: This model successfully recapitulates the clinicopathological and pathophysiological characteristics of patients with fourth ventricle hemorrhage and can be utilized for further investigation into the pathophysiological mechanisms underlying posthemorrhagic hydrocephalus and perilesional brainstem tissue injury.

Keywords

animal model / brainstem injury / fourth ventricle hemorrhage / hydrocephalus / intraventricular hemorrhage

References

[1] Essibayi MA, Ibrahim Abdallah O, Mortezaei A, et al. Natural history, pathophysiology, and recent management modalities of intraventricular hemorrhage. J Intensive Care Med. 2024; 39(9): 813-819.

[2] Sanchez-Caro JM, de Ubago ID, de Celis Ruiz E, et al. Transient focal neurological events in cerebral amyloid angiopathy and the long-term risk of intracerebral hemorrhage and death: a systematic review and meta-analysis. JAMA Neurol. 2022; 79(1): 38-47.

[3] Sheth KN. Spontaneous intracerebral hemorrhage. N Engl J Med. 2022; 387(17): 1589-1596.

[4] Seiffge DJ, Fandler-Hofler S, Du Y, et al. Intracerebral haemorrhage - mechanisms, diagnosis and prospects for treatment and prevention. Nat Rev Neurol. 2024; 20(12): 708-723.

[5] Shah VA, Thompson RE, Yenokyan G, et al. One-year outcome trajectories and factors associated with functional recovery among survivors of intracerebral and intraventricular hemorrhage with initial severe disability. JAMA Neurol. 2022; 79(9): 856-868.

[6] Lv XN, Cheng J, Liu XY, et al. Ultraearly intraventricular hemorrhage growth predicts early neurologic deterioration and poor functional outcome after acute intracerebral hemorrhage. J Am Heart Assoc. 2023; 12(21): e031214.

[7] Mustanoja S, Satopaa J, Meretoja A, et al. Extent of secondary intraventricular hemorrhage is an independent predictor of outcomes in intracerebral hemorrhage: data from the Helsinki ICH study. Int J Stroke. 2015; 10(4): 576-581.

[8] Shapiro SA, Campbell RL, Scully T. Hemorrhagic dilation of the fourth ventricle: an ominous predictor. J Neurosurg. 1994; 80(5): 805-809.

[9] Kim YS, Ryu HS, Kim TS, Joo SP. Direct removal of fourth ventricle hematoma in massive intraventricular hemorrhage. J Korean Neurosurg Soc. 2022; 65(2): 325-330.

[10] Li Y, Zhang J. Animal models of stroke. Animal Model Exp Med. 2021; 4(3): 204-219.

[11] Alharbi BM, Tso MK, Macdonald RL. Animal models of spontaneous intracerebral hemorrhage. Neurol Res. 2016; 38(5): 448-455.

[12] Chen J, Zhang D, Li Z, et al. Lateral ventricular volume asymmetry predicts poor outcome after spontaneous intracerebral hemorrhage. World Neurosurg. 2018; 110: e958-e964.

[13] Chen S, Gu J, Gao F. Application of cerebellomedullary fissure approach in the treatment of ventricle hemorrhage with fourth ventricle casting. Zhejiang J Trauma Surg. 2022; 27(6): 1095-1097.

[14] Marinkovic I, Strbian D, Mattila OS, Abo-Ramadan U, Tatlisumak T. A novel combined model of intracerebral and intraventricular hemorrhage using autologous blood-injection in rats. Neuroscience. 2014; 272: 286-294.

[15] Holste KG, Xia F, Ye F, Keep RF, Xi G. Mechanisms of neuroinflammation in hydrocephalus after intraventricular hemorrhage: a review. Fluids Barriers CNS. 2022; 19(1): 28.

[16] Zhang Z, Tan Q, Guo P, et al. NLRP3 inflammasome-mediated choroid plexus hypersecretion contributes to hydrocephalus after intraventricular hemorrhage via phosphorylated NKCC1 channels. J Neuroinflammation. 2022; 19(1): 163.

[17] Zhang Q, Chen Y, Li Y, et al. Neutrophil extracellular trap-mediated impairment of meningeal lymphatic drainage exacerbates secondary hydrocephalus after intraventricular hemorrhage. Theranostics. 2024; 14(5): 1909-1938.

[18] Puy L, Parry-Jones AR, Sandset EC, Dowlatshahi D, Ziai W, Cordonnier C. Intracerebral haemorrhage. Nat Rev Dis Primers. 2023; 9(1): 14.

[19] Wang C, Bai J, He Q, et al. Therapy management and outcome of acute hydrocephalus secondary to intraventricular hemorrhage in adults. Chin Neurosurg J. 2024; 10(1): 17.

[20] Kamal K, Keiter JA, Binyamin TR, et al. Mechanical injury and blood are drivers of spatial memory deficits after rapid intraventricular hemorrhage. Neurobiol Dis. 2020; 145: 105084.

[21] Chen Y, Galea I, Macdonald RL, Wong GKC, Zhang JH. Rethinking the initial changes in subarachnoid haemorrhage: focusing on real-time metabolism during early brain injury. EBioMedicine. 2022; 83: 104223.

[22] Zhang Z, Guo P, Liang L, et al. NLRP3-dependent lipid droplet formation contributes to posthemorrhagic hydrocephalus by increasing the permeability of the blood-cerebrospinal fluid barrier in the choroid plexus. Exp Mol Med. 2023; 55(3): 574-586.

[23] Wan Y, Fu X, Zhang T, Hua Y, Keep RF, Xi G. Choroid plexus immune cell response in murine hydrocephalus induced by intraventricular hemorrhage. Fluids Barriers CNS. 2024; 21(1): 37.

[24] Garton T, Keep RF, Wilkinson DA, et al. Intraventricular hemorrhage: the role of blood components in secondary injury and hydrocephalus. Transl Stroke Res. 2016; 7(6): 447-451.

[25] Chen Q, Tang J, Tan L, et al. Intracerebral hematoma contributes to hydrocephalus after intraventricular hemorrhage via aggravating iron accumulation. Stroke. 2015; 46(10): 2902-2908.

[26] Wan Y, Gao F, Ye F, et al. Effects of aging on hydrocephalus after intraventricular hemorrhage. Fluids Barriers CNS. 2020; 17(1): 8.

RIGHTS & PERMISSIONS

2025 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.