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. 2024 Nov;30(11):e70113.
doi: 10.1111/cns.70113.

The Neuroprotection of 1,2,4-Triazole Derivative by Inhibiting Inflammation and Protecting BBB Integrity in Acute Ischemic Stroke

Xuan Liu  1 , Jingning Luo  1 , Jianwen Chen  1 , Ping Huang  1 , Gongyun He  1 , Xueshi Ye  1 , Ruiqi Su  1 , Yaoqiang Lao  1 , Yang Wang  1 , Xiangjun He  1 , Jingxia Zhang  1
Affiliations

The Neuroprotection of 1,2,4-Triazole Derivative by Inhibiting Inflammation and Protecting BBB Integrity in Acute Ischemic Stroke

Xuan Liu et al. CNS Neurosci Ther. 2024 Nov.

Abstract

Background: The oxidative stress and neuroinflammation are important factors in acute ischemic stroke (AIS). Our former study showed the 1,2,4- triazole derivative (SYS18) had obviously neuroprotection by anti- oxidative stress on rat middle cerebral artery occlusion (MCAO) model.

Aim: In this study, we continue to investigate its neuroprotection by anti-inflammatory effects and protecting BBB integrity in AIS.

Methods and results: First, its effect on acute inflammation was evaluated by the mice model of increased peritoneal capillary permeability. Then, the MCAO cerebral edema models were built to evaluate its neuroprotection by reducing the neurological score, cerebral edema, improving the biochemical indicators, and pathological damage of brain tissue. At the same time, its protection on blood-brain barrier (BBB) integrity was proved by decreasing the BBB permeability and inhibiting glycocalyx degradation and regulating the BBB tight junction proteins expression of matrix metalloproteinase- 9 (MMP- 9) and claudin- 5 in brain tissue. Meanwhile, pharmacokinetic experiments showed that the compound had good BBB penetration. It has some advantages in the intensity of efficacy compared with the marketed drug edaravone.

Conclusion: Based on these findings, SYS18 has a strong potential to become a neuroprotectant in the future.

Keywords: 1,3,5‐triphenyl‐1,2,4‐triazole derivative; blood–brain barrier; glycocalyx; inflammatory.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Design of triazole derivatives.
FIGURE 2
FIGURE 2
The chemical structure of SYS18.
FIGURE 3
FIGURE 3
Anti‐inflammatory effects of SYS18 on acetic acid‐induced peritoneal capillary permeability increase models; n = 9–10; data are presented as mean ± SD. Data were analyzed by Mann–Whitney U test or Kruskal–Wallis rank sum test, # p < 0.05 vs. control group; *p < 0.05 vs. model group; **p < 0.01 vs. model group.
FIGURE 4
FIGURE 4
SYS18 alleviated neurological injury and cerebral edema. (A) The neurological status of the animals was evaluated by Zea‐Longa scoring criteria. n = 19–24, data were analyzed by Mann–Whitney U test or Kruskal–Wallis rank sum test. (B) SYS18 reduced brain water content after ischemic stroke, n = 6–10. (C) Brain edema volume after ischemic stroke in T2‐weighted MRI, n = 3, SYS18 = 30 mg/kg. (D) Brain edema volume percentage in T2‐weighted MRI. Results were expressed as mean ± SD. Measurement data were analyzed by one‐way analysis of variance combined with Dunnett's multiple comparison method. #### p < 0.0001 vs. sham group; *p < 0.05 vs. model group; **p < 0.01 vs. model group; ****p < 0.0001 vs. model group.
FIGURE 5
FIGURE 5
Effects of SYS18 on serum biochemical indicators in MCAO cerebral edema model. (A) MDA content in serum; (B) SOD activity in serum; (C) TNF‐α content in serum; (D) IL‐1β content in serum; n = 6. Data were presented as mean ± SD. Measurement data were analyzed by one‐way analysis of variance combined with Dunnett's multiple comparison method, ### p < 0.001 vs. sham group; #### p < 0.0001 vs. sham group; *p < 0.05 vs. model group; **p < 0.01 vs. model group; ***p < 0.001 vs. model group.
FIGURE 6
FIGURE 6
SYS18 improved neural tissue morphology in the cerebral cortex after ischemia–reperfusion. The cytoplasm was stained in red, and the nucleus was stained in blue. n = 3, observe in 400× inverted microscope, scale bar = 100 μm.
FIGURE 7
FIGURE 7
SYS18 attenuated BBB damage after ischemia–reperfusion injury. (A) Representative image of Evans blue content in brain. (B) Evans blue content in brain. BBB permeability was evaluated by Evans blue extravasation. n = 6–7. Data were expressed as mean ± SD. Measurement data were analyzed by one‐way analysis of variance combined with Dunnett's multiple comparison method. ### p < 0.001 vs. sham group; *p < 0.05 vs. model group.
FIGURE 8
FIGURE 8
Effects of SYS18 on endothelial glycocalyx in ischemia–reperfusion injury. (A) syndecan‐1 content in brain; (B) syndecan‐1 content in serum; (C) HPSE content in brain; (D) HS content in serum; n = 6. Data were presented as mean ± SD and were analyzed by one‐way analysis of variance combined with Dunnett's multiple comparison method. ### p < 0.001 vs. sham group; #### p < 0.0001 vs. sham group; *p < 0.05 vs. model control group; **p < 0.01 vs. model control group, ****p < 0.0001 vs. model control group.
FIGURE 9
FIGURE 9
(A) Immunofluorescence of claudin‐5 expression in each model; (B) Immunofluorescence of MMP‐9 expression in each model. Scale bar = 100 μm (observe in 400× inverted microscope); (C) Mean fluorescence intensity of claudin‐5; (D) Mean fluorescence intensity of MMP‐9. ### p < 0.001 vs. sham group; *p < 0.05 vs. model group; **p < 0.01 vs. model group; ***p < 0.001 vs. model group.
FIGURE 10
FIGURE 10
Blood and brain drug concentrations in rats after intraperitoneal injection of SYS18 (A) Comparison of SYS18 concentrations in blood and brain; (B) drug‐time curve of the SYS18 in the blood and brain.
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