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Journal of Peking University (Health Sciences) ›› 2024, Vol. 56 ›› Issue (3): 487-494. doi: 10.19723/j.issn.1671-167X.2024.03.016

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Ursolic acid improved demyelination and interstitial fluid drainage disorders in schizophrenia mice

Ren LONG1,Xin MAO2,Tianzi GAO1,Qian XIE2,Hanbo TAN1,Ziyin LI1,Hongbin HAN1,2,*(),Lan YUAN1,*()   

  1. 1. Department of Medical Imaging Technology, Institute of Medical Technology, Peking University & Beijing Key Lab of Magnetic Resonance Imaging Device and Technique, Beijing 100191, China
    2. Department of Radiology, Peking Univer-sity Third Hispital, Beijing 100191, China
  • Received:2023-04-20 Online:2024-06-18 Published:2024-06-12
  • Contact: Hongbin HAN,Lan YUAN E-mail:hanhongbin@bjmu.edu.cn;yuan_lan@bjmu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(62394310);the National Natural Science Foundation of China(62394312);the National Natural Science Foundation of China(62394314)

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Abstract:

Objective: To unveil the pathological changes associated with demyelination in schizophrenia (SZ) and its consequential impact on interstitial fluid (ISF) drainage, and to investigate the therapeutic efficacy of ursolic acid (UA) in treating demyelination and the ensuing abnormalities in ISF drainage in SZ. Methods: Female C57BL/6J mice, aged 6-8 weeks and weighing (20±2) g, were randomly divided into three groups: control, SZ model, and UA treatment. The control group received intraperitoneal injection (ip) of physiological saline and intragastric administration (ig) of 1% carboxymethylcellulose sodium (CMC-Na). The SZ model group was subjected to ip injection of 2 mg/kg dizocilpine maleate (MK-801) and ig administration of 1% CMC-Na. The UA treatment group underwent ig administration of 25 mg/kg UA and ip injection of 2 mg/kg MK-801. The treatment group received UA pretreatment via ig administration for one week, followed by a two-week drug intervention for all the three groups. Behavioral assessments, including the open field test and prepulse inhibition experiment, were conducted post-modeling. Subsequently, changes in the ISF partition drainage were investigated through fluorescent tracer injection into specific brain regions. Immunofluorescence analysis was employed to examine alterations in aquaporin 4 (AQP4) polarity distribution in the brain and changes in protein expression. Myelin reflex imaging using Laser Scanning Confocal Microscopy (LSCM) was utilized to study modifications in myelin within the mouse brain. Quantitative data underwent one-way ANOVA, followed by TukeyHSD for post hoc pairwise comparisons between the groups. Results: The open field test revealed a significantly longer total distance [(7 949.39±1 140.55) cm vs. (2 831.01±1 212.72) cm, P < 0.001] and increased central area duration [(88.43±22.06) s vs. (56.85±18.58) s, P=0.011] for the SZ model group compared with the controls. The UA treatment group exhibited signifi-cantly reduced total distance [(2 415.80±646.95) cm vs. (7 949.39±1 140.55) cm, P < 0.001] and increased central area duration [(54.78±11.66) s vs. (88.43±22.06) s, P=0.007] compared with the model group. Prepulse inhibition test results demonstrated a markedly lower inhibition rate of the startle reflex in the model group relative to the controls (P < 0.001 for both), with the treatment group displaying significant improvement (P < 0.001 for both). Myelin sheath analysis indicated significant demyelination in the model group, while UA treatment reversed this effect. Fluorescence tracing exhibited a significantly larger tracer diffusion area towards the rostral cortex and reflux area towards the caudal thalamus in the model group relative to the controls [(13.93±3.35) mm2 vs. (2.79±0.94) mm2, P < 0.001 for diffusion area; (2.48±0.38) mm2 vs. (0.05±0.12) mm2, P < 0.001 for reflux area], with significant impairment of drainage in brain regions. The treatment group demonstrated significantly reduced tracer diffusion and reflux areas [(7.93±2.48) mm2 vs. (13.93±3.35) mm2, P < 0.001 for diffusion area; (0.50±0.30) mm2 vs. (2.48±0.38) mm2, P < 0.001 for reflux area]. Immunofluorescence staining revealed disrupted AQP4 polarity distribution and reduced AQP4 protein expression in the model group compared with the controls [(3 663.88±733.77) μm2 vs. (13 354.92±4 054.05) μm2, P < 0.001]. The treatment group exhibited restored AQP4 polarity distribution and elevated AQP4 protein expression [(11 104.68±3 200.04) μm2 vs. (3 663.88±733.77) μm2, P < 0.001]. Conclusion: UA intervention ameliorates behavioral performance in SZ mice, Thus alleviating hyperactivity and anxiety symptoms and restoring sensorimotor gating function. The underlying mechanism may involve the improvement of demyelination and ISF drainage dysregulation in SZ mice.

Key words: Schizophrenia, Brain interstitial fluid, Demyelination, Ursolic acid

CLC Number: 

  • R285.5

Figure 1

Simplified schema of drug intervention design Drug intervention lasted for a total of 21 days, with pretreatment in the first week and animal modeling in the 2 to 3 weeks. Behavioral tests were conducted after the modeling was completed. UA, ursolic acid; MK-801, dizocilpine maleate; ip, intraperitoneal injection; ig, intragastric."

Figure 2

Effect of UA and MK-801 intervention on mice body weight Comparing the differences in weight changes among three groups using analysis of variance; n=7/group; error bar represents the standard deviation; * P < 0.05, ☆ P < 0.01. UA, ursolic acid; MK-801, dizocilpine maleate."

Figure 3

Effects of UA and MK-801 interventions on spontaneous activity and depressive mood in mice A, mice movement trajectory map; B, statistical comparison of total exercise distance; C, statistical comparison of time in open field center; n=7/group; error bar represents the standard deviation, * P < 0.05, ☆ P < 0.01, compared with Sham+vehicle group; # P < 0.01, compared with MK-801+vehicle group. UA, ursolic acid; MK-801, dizocilpine maleate."

Figure 4

Effects of UA and MK-801 interventions on sensorimotor gating in mice A, flow chart of prepulse inhibition experiment; B, statistics of shock reflection amplitude inhibition rate; n = 6－10; error bar represents the standard deviation; PPI(%), inhibitory rate of prepulse on the amplitude of startle stimulus; PPI3%, PPI6%, and PPI12% respectively refer to the inhibition rate of shock reflection amplitude when the pre pulse intensity is 73 dB, 76 dB, and 82 dB; ☆ P < 0.01, compared with Sham+vehicle group, # P < 0.01, compared with MK-801+vehicle group. UA, ursolic acid; MK-801, dizocilpine maleate."

Figure 5

Effects of UA and MK-801 intervention on the myelin sheath in mice A, compact myelin structure between caudate nucleus and thalamus(scale bar=1.5 mm); the dashed area is the ISF drainage barrier; B, changes in the density of myelin sheath in the inner capsule area (scale bar=0.5 mm); C, injury of myelinated fiber bundles(scale bar=50 μm); arrow indicate significant demyelinating pathological changes in the model group. UA, ursolic acid; MK-801, dizocilpine maleate."

Figure 6

Effects of UA and MK-801 intervention on ISF drainage in mice Fluorescent tracer images (scale bar=1.5 mm). UA, ursolic acid; MK-801, dizocilpine maleate."

Figure 7

Comparison of AQP4 expression between groups AQP4 immunofluorescence images (scale bar=250 μm). UA, ursolic acid; MK-801, dizocilpine maleate."

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