Abstract
Stroke is the second leading cause of death globally. Cognitive dysfunction is a common complication of stroke, which seriously affects the patient’s quality of life. Previous studies have shown that the expression of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel is closely related to ischemia-reperfusion (IR) injury and subsequent cognitive impairment. We also found that ZD7288, a specific inhibitor of the HCN channel, attenuated IR injury during short-term reperfusion. Since apoptosis can induce cell necrosis and aggravate cognitive impairment after IR, the purpose of this study is to define whether ZD7288 could improve cognitive impairment after prolonged cerebral reperfusion in rats by regulating apoptotic pathways. Our data indicated that ZD7288 can ameliorate spatial cognitive behavior and synaptic plasticity, protect the morphology of hippocampal neurons, and alleviate hippocampal apoptotic cells in IR rats. This effect may be related to down-regulating the expressions of pro-apoptotic proteins such as AIF, p53, Bax, and Caspase-3, and increasing the ratio of Bcl-2/Bax. Taken together, it suggested that inhibition of the HCN channel improves cognitive impairment after IR correlated with its regulation of apoptotic pathways.
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Data Availability
All data generated or analyzed during this study are included in this article. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- IR:
-
Ischemia-reperfusion
- LTP:
-
Long-term potentiation
- HCN:
-
Hyperpolarization-activated cyclic nucleotide-gated cation
- Ih:
-
Hyperpolarization-activated mixed cationic
- NMDAR:
-
N-methyl-D-aspartic acid receptor
- MCAO:
-
Middle cerebral artery occlusion
- fEPSP:
-
Field excitatory postsynaptic potential
- HFS:
-
High-frequency stimulus
- HE:
-
Hematoxylin-eosin
- BSA:
-
Bovine serum albumin
- IOD:
-
Integrated optical density
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (No. 82073824, No. 81371318, No. 82204837), General Program of Health Commission of Hubei Province (WJ2019M066), Zhejiang Province Natural Science Foundation (No. LQ23H290004 ).
Funding
This work was supported by the National Natural Science Foundation of China (No. 82073824, No. 81371318, No. 82204837), General Program of Health Commission of Hubei Province (WJ2019M066), Zhejiang Province Natural Science Foundation (No. LQ23H290004 ).
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CRediT Statement. Zhi He: Conception and design, Funding acquisition, Supervision; (ORCID: 0000-0001-7567-8287) Jue Liu: Data analysis, Methodology; (ORCID: 0000-0002-0338-2257) Xiao-Li Zeng: Data analysis, Methodology; (ORCID: 0009-0007-5683-8565) Jing-Hong fan: Software, Validation, Methodology; (ORCID: 0009-0002-1915-7449) Ke Wang: Data analysis; (ORCID: 0000-0002-2795-8556) Yue Chen: Data analysis; (ORCID: 0000-0002-7909-4606) Zi-Cheng li: Data analysis, Methodology; (ORCID: 0000-0001-8533-5325) Bo Zhao: Data analysis, Writing original draft. (ORCID: 0009-0004-0384-6789)
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He, Z., Liu, J., Zeng, XL. et al. Inhibition of hyperpolarization-activated cyclic nucleotide-gated cation channel attenuates cerebral ischemia reperfusion-induced impairment of learning and memory by regulating apoptotic pathway. Metab Brain Dis 38, 2751–2763 (2023). https://doi.org/10.1007/s11011-023-01306-3
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DOI: https://doi.org/10.1007/s11011-023-01306-3