Dihydroergotamine ameliorates synaptic atrophy in Alzheimer’s disease states and its effect on cognitive function

CHEN Peipei; WEI Jie; LIU Xiaoquan; LIU Haochen

doi:10.11665/j.issn.1000-5048.2023032002

Journal of China Pharmaceutical University > 2023 > 54(4): 501-510. > DOI: 10.11665/j.issn.1000-5048.2023032002

CHEN Peipei, WEI Jie, LIU Xiaoquan, LIU Haochen. Dihydroergotamine ameliorates synaptic atrophy in Alzheimer’s disease states and its effect on cognitive function[J]. Journal of China Pharmaceutical University, 2023, 54(4): 501-510. DOI: 10.11665/j.issn.1000-5048.2023032002

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Dihydroergotamine ameliorates synaptic atrophy in Alzheimer’s disease states and its effect on cognitive function

Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 211198, China

Funds: This study was supported by the National Natural Science Foundation of China (No.81903703)

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Received Date: March 19, 2023
Revised Date: August 07, 2023

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Abstract

Studies suggest that synaptic damage is closely associated with cognitive dysfunction, and lemur tyrosine kinase 1 (LMTK1) is a key kinase that affects synaptic growth. Dihydroergotamine (DHE) is an ergot alkaloid derivative with high biological activity, which could regulate cognition, memory processing and motor control.This study aims to investigate the effect of DHE on synapse atrophy and plasticity as well as cognition in Alzheimer’s disease (AD) model animals.SAMR1 mice were selected as control group (n = 12).SAMP8 mice were randomly divided into 3 groups (n = 12 for each group):AD group, DHE low-dose group and high-dose group.The DHE groups were injected DHE intraperitoneally daily for 8 weeks.Immunofluorescence experiments, Golgi staining experiment, electrophysiological experiment, Morris water maze experiment (MWM) and Western blot experiment were conducted to investigate the effect of DHE on synaptic morphology, synaptic plasticity, cognitive function as well as the phosphorylation level of LMTK1 downstream TBC1D9B in AD model mice.Subsequently, the LMTK1 silencing and overexpression cells were constructed.Immunofluorescence experiments were used to study the effect of DHE on synaptic length of nerve cell after LMTK1 silencing and overexpression.In the hippocampus of AD mice, the postsynaptic marker PSD95 was significantly increased after DHE administration, which suggested that DHE could increase the synaptic density. In Golgi staining experiment, synaptic atrophy was observed in the hippocampal of AD mice, which could be improved by high-dose DHE.Compared with normal mice, the long-term potentiation (LTP) level of AD model mice was significantly reduced (P < 0.000 1), DHE could increase LTP significantly.The MWM experiment further showed that DHE could improve cognitive function in AD mice.WB experiments showed that the level of P-LMTK1 in the hippocampus of AD mice increased significantly, and the level of downstream P-TBC1D9B decreased significantly after DHE administration.Cell immunofluorescence experiments in vitro had shown that DHE significantly improved synaptic atrophy in overexpressed C17.2 cells, while its improvement disappeared when LMTK1 was silenced. This research suggests DHE may improve synaptic atrophy and cognitive dysfunction in AD by targeting on LMTK1.
- dihydroergotamine,
- Alzheimer’s disease,
- synapse,
- cognitive function,
- lemur tyrosine kinase 1 (LMTK1)

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