Paclitaxel Induces Neurotoxicity by Disrupting Tricarboxylic Acid Cycle Metabolic Balance in the Mouse Hippocampus
Objective. It is well known that paclitaxel (PTX)-induced neurotoxicity seriously affects the quality of life of patients and is the main reason for reducing the dose of chemotherapy or even stopping chemotherapy. The current data are limited, and further information is required for practice and ver...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Hindawi Limited
2023-01-01
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| Series: | Journal of Toxicology |
| Online Access: | http://dx.doi.org/10.1155/2023/5660481 |
| _version_ | 1797744153288769536 |
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| author | Xi Liu Changmeng Cui Wenxue Sun Junjun Meng Jinxiu Guo Linlin Wu Beibei Chen Dehua Liao Pei Jiang |
| author_facet | Xi Liu Changmeng Cui Wenxue Sun Junjun Meng Jinxiu Guo Linlin Wu Beibei Chen Dehua Liao Pei Jiang |
| author_sort | Xi Liu |
| collection | DOAJ |
| description | Objective. It is well known that paclitaxel (PTX)-induced neurotoxicity seriously affects the quality of life of patients and is the main reason for reducing the dose of chemotherapy or even stopping chemotherapy. The current data are limited, and further information is required for practice and verification. The aims of this study were to clarify the molecular mechanism underlying PTX-induced neurotoxicity by combining in vivo and in vitro metabolomics studies and provide new targets for the prevention and treatment of PTX-induced neurotoxicity. Methods. In the in vivo study, a PTX-induced neurotoxicity mouse model was established by intraperitoneal injection of PTX (6 mg/kg every three days) for two consecutive weeks. After verification by water maze tests and HE staining of pathological sections, hippocampal metabolites were measured and the differential metabolites and related metabolic pathways were identified by multivariate statistical analysis. In the in vitro study, we investigated the effects of PTX on mouse hippocampal neuron cells, assessing the concentration and time of administration by MTT assays. After modeling, the relevant metabolites in the TCA cycle were quantified by targeted metabolomics using stable isotope labeling. Finally, the key enzymes of the TCA cycle in tissues and cells were verified by RT-PCR. Results. Administration of PTX to model mice resulted in neurological damage, shown by both water-maze tests and hippocampal tissue sections. Twenty-four metabolites and five associated metabolic pathways were found to differ significantly between the hippocampal tissues of the model and control groups. These included metabolites and pathways related to the TCA cycle and pyruvate metabolism. Metabolomics analysis using stable isotope labeling showed significant changes in metabolites associated with the TCA cycle compared with the control group (P<0.05). Finally, RT-PCR verified that the expression of key enzymes in the TCA cycle was changed to different degrees in both hippocampal tissues and cells. Conclusion. Our results showed that PTX neurotoxicity in hippocampal tissue and neuron cells was associated with inhibition of the TCA cycle. This inhibition leads to brain insufficiency and impaired metabolism, resulting in various neurotoxic symptoms. |
| first_indexed | 2024-03-12T15:06:40Z |
| format | Article |
| id | doaj.art-ba37caadc2ae405392415e02ee1efed0 |
| institution | Directory Open Access Journal |
| issn | 1687-8205 |
| language | English |
| last_indexed | 2024-03-12T15:06:40Z |
| publishDate | 2023-01-01 |
| publisher | Hindawi Limited |
| record_format | Article |
| series | Journal of Toxicology |
| spelling | doaj.art-ba37caadc2ae405392415e02ee1efed02023-08-13T00:00:00ZengHindawi LimitedJournal of Toxicology1687-82052023-01-01202310.1155/2023/5660481Paclitaxel Induces Neurotoxicity by Disrupting Tricarboxylic Acid Cycle Metabolic Balance in the Mouse HippocampusXi Liu0Changmeng Cui1Wenxue Sun2Junjun Meng3Jinxiu Guo4Linlin Wu5Beibei Chen6Dehua Liao7Pei Jiang8Department of PharmacyDepartment of NeurosurgeryTranslational Pharmaceutical LaboratoryTranslational Pharmaceutical LaboratoryTranslational Pharmaceutical LaboratoryDepartment of OncologyADFA School of ScienceDepartment of PharmacyTranslational Pharmaceutical LaboratoryObjective. It is well known that paclitaxel (PTX)-induced neurotoxicity seriously affects the quality of life of patients and is the main reason for reducing the dose of chemotherapy or even stopping chemotherapy. The current data are limited, and further information is required for practice and verification. The aims of this study were to clarify the molecular mechanism underlying PTX-induced neurotoxicity by combining in vivo and in vitro metabolomics studies and provide new targets for the prevention and treatment of PTX-induced neurotoxicity. Methods. In the in vivo study, a PTX-induced neurotoxicity mouse model was established by intraperitoneal injection of PTX (6 mg/kg every three days) for two consecutive weeks. After verification by water maze tests and HE staining of pathological sections, hippocampal metabolites were measured and the differential metabolites and related metabolic pathways were identified by multivariate statistical analysis. In the in vitro study, we investigated the effects of PTX on mouse hippocampal neuron cells, assessing the concentration and time of administration by MTT assays. After modeling, the relevant metabolites in the TCA cycle were quantified by targeted metabolomics using stable isotope labeling. Finally, the key enzymes of the TCA cycle in tissues and cells were verified by RT-PCR. Results. Administration of PTX to model mice resulted in neurological damage, shown by both water-maze tests and hippocampal tissue sections. Twenty-four metabolites and five associated metabolic pathways were found to differ significantly between the hippocampal tissues of the model and control groups. These included metabolites and pathways related to the TCA cycle and pyruvate metabolism. Metabolomics analysis using stable isotope labeling showed significant changes in metabolites associated with the TCA cycle compared with the control group (P<0.05). Finally, RT-PCR verified that the expression of key enzymes in the TCA cycle was changed to different degrees in both hippocampal tissues and cells. Conclusion. Our results showed that PTX neurotoxicity in hippocampal tissue and neuron cells was associated with inhibition of the TCA cycle. This inhibition leads to brain insufficiency and impaired metabolism, resulting in various neurotoxic symptoms.http://dx.doi.org/10.1155/2023/5660481 |
| spellingShingle | Xi Liu Changmeng Cui Wenxue Sun Junjun Meng Jinxiu Guo Linlin Wu Beibei Chen Dehua Liao Pei Jiang Paclitaxel Induces Neurotoxicity by Disrupting Tricarboxylic Acid Cycle Metabolic Balance in the Mouse Hippocampus Journal of Toxicology |
| title | Paclitaxel Induces Neurotoxicity by Disrupting Tricarboxylic Acid Cycle Metabolic Balance in the Mouse Hippocampus |
| title_full | Paclitaxel Induces Neurotoxicity by Disrupting Tricarboxylic Acid Cycle Metabolic Balance in the Mouse Hippocampus |
| title_fullStr | Paclitaxel Induces Neurotoxicity by Disrupting Tricarboxylic Acid Cycle Metabolic Balance in the Mouse Hippocampus |
| title_full_unstemmed | Paclitaxel Induces Neurotoxicity by Disrupting Tricarboxylic Acid Cycle Metabolic Balance in the Mouse Hippocampus |
| title_short | Paclitaxel Induces Neurotoxicity by Disrupting Tricarboxylic Acid Cycle Metabolic Balance in the Mouse Hippocampus |
| title_sort | paclitaxel induces neurotoxicity by disrupting tricarboxylic acid cycle metabolic balance in the mouse hippocampus |
| url | http://dx.doi.org/10.1155/2023/5660481 |
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