ZD7288 ameliorates long-term cerebral ischemia reperfusion-induced deterioration of spatial memory by regulating the expressions of NMDA receptor subunits in rats
Abstract To study the effect of inhibition of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) on spatial memory with cerebral ischemia-reperfusion (IR) in rats, the middle cerebral artery occlusion was performed to induce the IR injury. ZD7288 (5 µg/µl) and MK-801 (100 µg/µl...
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41598-025-03172-8 |
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| author | Zhi He Xiao-Jiao Chu Xiao-Li Zeng Xiao-Xue Zhang Jing Chen Ke Wang Yue Chen Zi-Cheng Li Bo Zhao |
| author_facet | Zhi He Xiao-Jiao Chu Xiao-Li Zeng Xiao-Xue Zhang Jing Chen Ke Wang Yue Chen Zi-Cheng Li Bo Zhao |
| author_sort | Zhi He |
| collection | DOAJ |
| description | Abstract To study the effect of inhibition of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) on spatial memory with cerebral ischemia-reperfusion (IR) in rats, the middle cerebral artery occlusion was performed to induce the IR injury. ZD7288 (5 µg/µl) and MK-801 (100 µg/µl) were administrated by lateral ventricular injection. Except for the sham group, all other groups were subjected to ischemia for 2 h followed by reperfusion for 4 weeks. The neurological impairment was evaluated using the neurological deficit score, and the Morris water maze detected changes in spatial memory. The cerebral infarction volume was determined by TTC staining, and the morphology and number of hippocampal neurons on the ischemic side were observed through HE staining. Immunoblotting and qPCR were used to detect the expressions of HCN1, HCN2, and N-methyl-D-aspartic acid receptor (NMDAR) subunits in the hippocampus. The expression changes of NMDAR subunits were applied by immunohistochemistry in different hippocampus regions. Our study found that ZD7288 could improve the spatial memory deficits induced by IR and exert neuroprotective effects. The possible mechanism is related to the fact that ZD7288 regulates the expression of various subunits of NMDAR by inhibiting HCN, including its effect on their phosphorylation states. |
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| id | doaj-art-aeeb9f6404a5443e9dd23f9d2158db26 |
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| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-aeeb9f6404a5443e9dd23f9d2158db262025-08-20T03:16:50ZengNature PortfolioScientific Reports2045-23222025-05-0115111310.1038/s41598-025-03172-8ZD7288 ameliorates long-term cerebral ischemia reperfusion-induced deterioration of spatial memory by regulating the expressions of NMDA receptor subunits in ratsZhi He0Xiao-Jiao Chu1Xiao-Li Zeng2Xiao-Xue Zhang3Jing Chen4Ke Wang5Yue Chen6Zi-Cheng Li7Bo Zhao8Department of Pharmacology, College of Medicine, Jiaxing UniversityThird-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges UniversityThird-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges UniversityDepartment of Clinical Laboratory, Wuhan Fourth HospitalThird-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges UniversityDepartment of Pharmacology, College of Medicine, Jiaxing UniversityDepartment of Pharmacology, College of Medicine, Jiaxing UniversityThird-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges UniversityThird-Grade Pharmacological Laboratory on Traditional Chinese Medicine, State Administration of Traditional Chinese Medicine, China Three Gorges UniversityAbstract To study the effect of inhibition of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) on spatial memory with cerebral ischemia-reperfusion (IR) in rats, the middle cerebral artery occlusion was performed to induce the IR injury. ZD7288 (5 µg/µl) and MK-801 (100 µg/µl) were administrated by lateral ventricular injection. Except for the sham group, all other groups were subjected to ischemia for 2 h followed by reperfusion for 4 weeks. The neurological impairment was evaluated using the neurological deficit score, and the Morris water maze detected changes in spatial memory. The cerebral infarction volume was determined by TTC staining, and the morphology and number of hippocampal neurons on the ischemic side were observed through HE staining. Immunoblotting and qPCR were used to detect the expressions of HCN1, HCN2, and N-methyl-D-aspartic acid receptor (NMDAR) subunits in the hippocampus. The expression changes of NMDAR subunits were applied by immunohistochemistry in different hippocampus regions. Our study found that ZD7288 could improve the spatial memory deficits induced by IR and exert neuroprotective effects. The possible mechanism is related to the fact that ZD7288 regulates the expression of various subunits of NMDAR by inhibiting HCN, including its effect on their phosphorylation states.https://doi.org/10.1038/s41598-025-03172-8StrokeHCN channelZ7288NMDA receptorSpatial memoryHippocampus |
| spellingShingle | Zhi He Xiao-Jiao Chu Xiao-Li Zeng Xiao-Xue Zhang Jing Chen Ke Wang Yue Chen Zi-Cheng Li Bo Zhao ZD7288 ameliorates long-term cerebral ischemia reperfusion-induced deterioration of spatial memory by regulating the expressions of NMDA receptor subunits in rats Scientific Reports Stroke HCN channel Z7288 NMDA receptor Spatial memory Hippocampus |
| title | ZD7288 ameliorates long-term cerebral ischemia reperfusion-induced deterioration of spatial memory by regulating the expressions of NMDA receptor subunits in rats |
| title_full | ZD7288 ameliorates long-term cerebral ischemia reperfusion-induced deterioration of spatial memory by regulating the expressions of NMDA receptor subunits in rats |
| title_fullStr | ZD7288 ameliorates long-term cerebral ischemia reperfusion-induced deterioration of spatial memory by regulating the expressions of NMDA receptor subunits in rats |
| title_full_unstemmed | ZD7288 ameliorates long-term cerebral ischemia reperfusion-induced deterioration of spatial memory by regulating the expressions of NMDA receptor subunits in rats |
| title_short | ZD7288 ameliorates long-term cerebral ischemia reperfusion-induced deterioration of spatial memory by regulating the expressions of NMDA receptor subunits in rats |
| title_sort | zd7288 ameliorates long term cerebral ischemia reperfusion induced deterioration of spatial memory by regulating the expressions of nmda receptor subunits in rats |
| topic | Stroke HCN channel Z7288 NMDA receptor Spatial memory Hippocampus |
| url | https://doi.org/10.1038/s41598-025-03172-8 |
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