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. 2021 Nov 23;13(22):24815-24828.
doi: 10.18632/aging.203717. Epub 2021 Nov 23.

Atorvastatin combined with dexamethasone promote hematoma absorption in an optimized rat model of chronic subdural hematoma

Dong Wang  1   2 , Yueshan Fan  1   2   3 , Jun Ma  1   2 , Chuang Gao  1   2 , Xuanhui Liu  1   2   3 , Zilong Zhao  1   2 , Huijie Wei  1   2 , Guili Yang  1   2 , Jinhao Huang  1   2 , Rongcai Jiang  1   2 , Jianning Zhang  1   2
Affiliations

Atorvastatin combined with dexamethasone promote hematoma absorption in an optimized rat model of chronic subdural hematoma

Dong Wang et al. Aging (Albany NY). .

Abstract

Previous studies found that atorvastatin and dexamethasone were effective in promoting the absorption of chronic subdural hematoma. In this study, we aimed to investigate the effect of pharmacotherapy in an optimized rat model of chronic subdural hematoma. Rat model of chronic subdural hematoma via a bEnd.3 cell and Matrigel mix was established and dynamic changes in different drug treatment groups were tested. The hematoma gradually increased, peaked on the fifth day (263.8±52.85 μl), and was completely absorbed in two weeks. Notably, Kruppelle-like factor 2 expression was significantly decreased with increasing hematoma volume, and then increased in the repair period. The expression of IL-10 was increased and peaked on 7 days, and then decreased at 14 days. The dynamic trends of IL-6, IL-8, MMP-9, and VEGF were also increased first and then decreased. Both monotherapy and the combined treatment by atorvastatin and dexamethasone could counteract the inflammatory activities, decrease hematoma permeability, and improve hematoma absorption, however, most prominent in combined group. The combined treatment could more effectively increase Kruppelle-like factor 2 and ZO-1 expression, attenuate the expression of NF-κb. Most importantly, the combined treatment enhanced the neural functional prognosis and reduced the mortality of chronic subdural hematoma rats. According to our results, the combined treatment could more effectively attenuate inflammatory. And it could also enhance angiogenic activities which could promote the stability of local function and structure of the hematoma cavity, reduce the hematoma volume and improve the outcomes of rats with chronic subdural hematoma than single treatments in the optimized chronic subdural hematoma model.

Keywords: CSDH; angiogenic processes; atorvastatin combined with low-dose dexamethasone treatment; inflammatory activities; optimized CSDH rat model.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Illustration of the rat model of CSDH. (A) The sphenoid burr hole was made using a modified drill, and the dura was punctured under a microscope. (a) The microscopic photograph of the burr hole. (B) Prepare the cell-matrix glue mixture for injection. Representative photomicrograph of the morphology of bEnd.3 cells under light microscope and Sigma-Aldrich Matrigel. (C) A photograph of the entire assembly comprised of a stereotaxic frame and a stereotaxic injector with a 20-gauge catheter. (c) Zooming diagram of model rat. (D) Schematic diagram of drilled sphenoid burr hole, punctured dural hole, and catheter perfusion.
Figure 2
Figure 2
The dynamic change in hematoma volume in the chronic subdural hematoma model. (A) The MRI (GRE sequence) in the IM group. The part circled in red is the mixture of Matrigel and cells located in the subdural cavity of the rat; at this time, there is no blood signal in the subdural cavity. (B–E) Dynamic MRI (GRE) on the 3rd, 5th, 7th and 14th days after the establishment of the model. The part circled in red is the hematoma formed by spontaneous hemorrhage in the subdural region, in which the thickness and volume of the hematoma peaked at 5 d post-injury. At 14 d, most of the hematoma had been absorbed. (F) The dynamic change in the hematoma volume of the rats after modeling. IM: immediately after modeling. ** indicates p < 0.01 compared with the IM group, and *** indicates p < 0.001 compared with the IM group. IM indicates immediate MRI images after the establishment of the model.
Figure 3
Figure 3
Dynamic changes in the expression of inflammatory factors and angiogenic factors in the capsule of rats with chronic subdural hematoma after modeling. (A) Changes in MMP-9 mRNA expression in the hematoma capsule at different timepoints after modeling. (B) Changes in VEGF mRNA expression in the hematoma capsule at different timepoints after modeling. (C) Changes in MMP-9 protein expression in the hematoma capsule detected by ELISAs at different timepoints after modeling. (D) Changes in VEGF protein expression in the hematoma capsule detected by ELISAs at different timepoints after modeling. (E) Changes in IL-6 protein expression in the hematoma capsule detected by ELISAs at different timepoints after modeling. (F) Changes in IL-8 protein expression in the hematoma capsule detected by ELISAs at different timepoints after modeling. (G) Changes in IL-10 protein expression in the hematoma capsule detected by ELISAs at different timepoints after modeling. IM: immediately after modeling. * p < 0.05 compared with the control group, ** p < 0.01 compared with the control group, *** p < 0.001 compared with the control group.
Figure 4
Figure 4
Changes in KLF-2 expression in the capsule of the chronic subdural hematoma model. (A) Changes in KLF-2 in the capsule of the hematoma at different timepoints after modeling. (B) The KLF-2 mRNA expression in the capsule of the hematoma detected by PCR at different timepoints after modeling. IM: immediately after modeling. * p < 0.05 compared with the control group, *** p < 0.001 compared with the IM group.
Figure 5
Figure 5
MRI and HE staining showed hematoma volume changes in different intervention groups on the 5th day after modeling. (A) Representative MRI (GRE) images of hematomas on the 5th day in the hematoma group. (B, C) Representative MRI (GRE) images of hematomas on the 5th day after treatment with atorvastatin and dexamethasone separately. (D) Representative MRI (GRE) images of hematomas on the 5th day in the atorvastatin + dexamethasone treatment group. (E) The changes in hematoma volume of the rats with CSDH after different treatments. (F–I) Typical images of growth appearances in different treatment groups after hematoma injury. (J–M) Representative H&E staining in different treatment groups after hematoma injury, bar =100 μm. * p < 0.05 compared with the control group, *** p < 0.001 compared with the control group, ## p<0.01 compared with the atorvastatin treatment group; †† p<0.01 compared with the dexamethasone treatment group.
Figure 6
Figure 6
Vascular permeability of the hematoma cavity in different intervention groups on the 5th day after modeling. Quantification of Evans blue in the different treatment groups after CSDH modeling. ** means p < 0.01 compared with the control group; *** means p < 0.001 compared with the control group; # p<0.05, compared with the single atorvastatin treatment group; † p<0.05, compared with the single dexamethasone treatment group.
Figure 7
Figure 7
Changes in the expression of inflammatory factors and angiogenic factors in different treatment groups after chronic subdural hematoma modeling. (A) Changes in the Ang-1/Ang-2 mRNA ratio in the hematoma capsule of different treatment group after modeling. (B) Changes in VEGF protein expression in the hematoma capsule of different treatment group after modeling. (C) Changes in MMP-9 protein expression in the hematoma capsule detected by ELISAs of different treatment group after modeling. (D) Changes in IL-6 protein expression in the hematoma capsule detected by ELISAs of different treatment group after modeling. (E) Changes in IL-8 protein expression in the hematoma capsule detected by ELISAs of different treatment group after modeling. (F) Changes in IL-10 protein expression in the hematoma capsule detected by ELISAs of different treatment group after modeling. * p < 0.05 compared with the control group, ** p < 0.01 compared with the control group, *** p < 0.001 compared with the control group; # p<0.05, compared with the single atorvastatin treatment group, ## p<0.01, compared with the single atorvastatin treatment group; † p<0.05, compared with the single dexamethasone treatment group; †† p<0.01, compared with the single dexamethasone treatment group.
Figure 8
Figure 8
Changes in ZO-1, KLF-2 and NF-κb expression in the capsule of the chronic subdural hematoma model in different treatment groups. (A) Changes in ZO-1, KLF-2 and NF-κb expression in the hematoma capsule in the different treatment groups after modeling. (B) The ZO-1, KLF-2 and NF-κb mRNA expression in the hematoma capsule detected by PCR in the different treatment groups after modeling. * p < 0.05 compared with the control group, *** p < 0.001 compared with the hematoma group. # indicates p<0.05, compared with the atorvastatin-only treatment group, ## indicates p<0.01, compared with the atorvastatin-only treatment group; † indicates p<0.05, compared with the dexamethasone-only treatment group; †† indicates p<0.01, compared with the dexamethasone-only treatment group.
Figure 9
Figure 9
Dynamic changes in the functional scores of the rats after different interventions. (A) The dynamic changes in corner turning test scores in different intervention groups. (B) The dynamic changes in forelimb-use asymmetry scores in different intervention groups. *Compared with the hematoma group, p < 0.05; ** compared with the hematoma group, p < 0.01; *** compared with the hematoma group, p < 0.001; # compared with the atorvastatin treatment group, p < 0.05; † indicates p<0.05, compared with the dexamethasone-only treatment group; †† indicates p<0.01, compared with the dexamethasone-only treatment group.
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