PT109 Ameliorates Cognitive Impairment in the Streptozotocin-induced Sporadic Alzheimer’S Disease Mice and Its Mechanisms
10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2021.0507
- VernacularTitle:PT109改善链脲佐菌素诱导的散发性阿尔茨海默病小鼠认知功能障碍的作用及机制
- Author:
Qiu-he CHEN
1
;
Ya-lin TU
1
;
Jia-wei HOU
2
;
Chen CHEN
1
;
Jun-feng LU
1
;
Rong-biao PI
2
Author Information
1. Department of Pharmacology & Toxicology， School of Pharmaceutical Sciences， Sun Yat-sen University， Guangzhou 510006， China
2. Department of Pharmacology， School of Medicine， Sun Yat-sen University， Shenzhen 518107， China
- Publication Type:Journal Article
- Keywords:
Alzheimer’s disease;
streptozotocin;
PT109;
multi-kinase inhibitor
- From:
Journal of Sun Yat-sen University(Medical Sciences)
2021;42(5):694-702
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo observe whether PT109 ［5-（1，2-dithiolan-3-yl）-N-（4-（isoquinolin-5-ylamino）cyclohexyl）pentanamide］ could improve the cognitive dysfunction in sporadic AD mice induced by lateral ventricular injection of streptozotocin and study the underlying mechanisms. MethodsThirty-two seven-week-old male C57BL/6 mice were randomly divided into 4 groups： control group （7 mice）， model group （7 mice）， PT109 low dosage group （9 mice） and PT109 high dosage group （9 mice）. To establish the sporadic Alzheimer’s disease， these mice were injected with intracerebroventricular streptozotocin on the first and third day （3 mg/kg， 5 μL per injection site）. Then PT109 （30， 100 mg·kg-1·d-1） was injected intraperitoneally. Two weeks later， Morris water maze and step through test were used to evaluate the effect of PT109 on the learning and memory ability of AD mice. The AD related indexes such as microglia， neurons， dendritic spines and phosphorylated Tau protein were detected by immunofluorescence， immunohistochemistry， western blotting and Golgi staining. ResultsThe behavioral experiments results showed that PT109 could improve the learning and memory impairment. The immunofluorescence and immunohistochemistry staining results showed that compared with model group， PT109 reduced the number of Iba1 positive cell in hippocampus region （low dosage： P <0.001， high dosage： P <0.001） and high dosage PT109 increased the total number of MAP2 and Tuj1 positive cell in hippocampus and cortex region （P <0.05， P <0.01）. The Golgi staining results showed that compared with model group， PT109 increased the density of dendritic spines （low dosage： P <0.001， high dosage： P <0.001）. The western blotting results showed that compared with model group， PT109 decreased the protein levels of NLRP3 （high dosage： P <0.05 ） and phosphorylated Tau protein （low dosage： P <0.05， high dosage： P <0.01 ）， and high dosage PT109 increased the protein levels of PSD95 （P <0.05） and phosphorylated GSK3β （P <0.05）. ConclusionPT109 could improve the learning and memory impairment of icv-STZ mice， which might be related to the regulation of GSK3β/Tau pathway.
