Paclitaxel Induces Cognitive Impairment Via Necroptosis, Decreased Synaptic Plasticity and M1 Polarisation of Microglia

Overview

Journal Pharm Biol

Specialties Pharmacology
Pharmacy

Date 2022 Aug 9

PMID 35944285

Authors

Miao Tang

Shuang Zhao

Jia-Xin Liu

Xin Liu

Yue-Xian Guo

Gui-Ying Wang

Xiu-Li Wang

Affiliations

Soon will be listed here.

Abstract

Context: Paclitaxel (PTX) leads to chemotherapy brain (chemo-brain) which is characterised by cognitive impairment. It has been reported that necroptosis is associated with cognitive impairment in some neurodegenerative diseases, but it is not clear whether it is related to the development of chemo-brain.

Objective: To investigate the role of necroptosis and related changes in PTX-induced cognitive impairment.

Materials And Methods: C57bl/6n mice were randomly divided into five groups: control, vehicle, and different concentrations of PTX (6, 8, 10 mg/kg). Two additional groups received pre-treatment with Gdcl3 or PBS through Intracerebroventricular (ICV) injection before PTX-treatment. Cognitive function, necroptosis, synaptic plasticity and microglia polarisation were analysed.

Results: PTX (10 mg/kg) induced significant cognitive impairment, accompanied by changes in synaptic plasticity, including decreased density of PSD95 (0.65-fold), BDNF (0.44-fold) and dendritic spines (0.57-fold). PTX induced necroptosis of 53.41% (RIP3) and 61.91% (MLKL) in hippocampal neurons, with high expression of RIP3 (1.58-fold) compared with the control group. MLKL (1.87-fold) exhibited the same trend, reaching a peak on the 14th day. The increased expression of iNOS (1.63-fold) and inflammatory factors such as TNF-α (1.85-fold) and IL-β (1.89-fold) compared to the control group suggests that M1 polarisation of microglia is involved in the process of cognitive impairment. Pre-treatment with Gdcl3 effectively reduced the number of microglia (0.50-fold), inhibited the release of TNF-α (0.73-fold) and IL-β (0.56-fold), and improved cognitive impairment.

Conclusion: We established a stable animal model of PTX-induced cognitive impairment and explored the underlying pathophysiological mechanism. These findings can guide the future treatment of chemo-brain.

Citing Articles

MCC950 Reduces the Anxiodepressive-like Behaviors and Memory Deficits Related to Paclitaxel-Induced Peripheral Neuropathy in Mice.

Martinez-Martel I, Negrini-Ferrari S, Pol O Antioxidants (Basel). 2025; 14(2).

PMID: 40002330 PMC: 11851537. DOI: 10.3390/antiox14020143.

Effects of preoperative neoadjuvant chemotherapy on postoperative delirium in patients with gynecological tumor surgery: an observational study.

Yang Y, Chen J, Wen Q, Jin G, Liu F, Yu L J Cancer Res Clin Oncol. 2024; 150(11):497.

PMID: 39542945 PMC: 11564223. DOI: 10.1007/s00432-024-06006-8.

Crosstalk of non-apoptotic RCD panel in hepatocellular carcinoma reveals the prognostic and therapeutic optimization.

Li S, Xu Y, Hu X, Chen H, Xi X, Long F iScience. 2024; 27(6):109901.

PMID: 38799554 PMC: 11126946. DOI: 10.1016/j.isci.2024.109901.

Potential of Natural Phenolic Compounds against Doxorubicin-Induced Chemobrain: Biological and Molecular Mechanisms Involved.

Serini S, Calviello G Antioxidants (Basel). 2024; 13(4).

PMID: 38671933 PMC: 11047710. DOI: 10.3390/antiox13040486.

Immune drivers of physiological and pathological pain.

Jain A, Hakim S, Woolf C J Exp Med. 2024; 221(5).

PMID: 38607420 PMC: 11010323. DOI: 10.1084/jem.20221687.

References

Malenka R, Bear M . LTP and LTD: an embarrassment of riches. Neuron. 2004; 44(1):5-21. DOI: 10.1016/j.neuron.2004.09.012. View

Shen J, Li Y, Qu C, Xu L, Sun H, Zhang J . The enriched environment ameliorates chronic unpredictable mild stress-induced depressive-like behaviors and cognitive impairment by activating the SIRT1/miR-134 signaling pathway in hippocampus. J Affect Disord. 2019; 248:81-90. DOI: 10.1016/j.jad.2019.01.031. View

Kim J, Bae H . Spontaneous Intracerebral Hemorrhage: Management. J Stroke. 2017; 19(1):28-39. PMC: 5307946. DOI: 10.5853/jos.2016.01935. View

Augusto-Oliveira M, Arrifano G, Takeda P, Lopes-Araujo A, Santos-Sacramento L, Anthony D . Astroglia-specific contributions to the regulation of synapses, cognition and behaviour. Neurosci Biobehav Rev. 2020; 118:331-357. DOI: 10.1016/j.neubiorev.2020.07.039. View

Atarod D, Eskandari-Sedighi G, Pazhoohi F, Karimian S, Khajeloo M, Riazi G . Microtubule Dynamicity Is More Important than Stability in Memory Formation: an In Vivo Study. J Mol Neurosci. 2015; 56(2):313-9. DOI: 10.1007/s12031-015-0535-4. View

Jang S, Chung H . Emerging Link between Alzheimer's Disease and Homeostatic Synaptic Plasticity. Neural Plast. 2016; 2016:7969272. PMC: 4785275. DOI: 10.1155/2016/7969272. View

Li Z, Zhao S, Zhang H, Liu P, Liu F, Guo Y . Proinflammatory Factors Mediate Paclitaxel-Induced Impairment of Learning and Memory. Mediators Inflamm. 2018; 2018:3941840. PMC: 5842689. DOI: 10.1155/2018/3941840. View

Suenaga J, Hu X, Pu H, Shi Y, Hassan S, Xu M . White matter injury and microglia/macrophage polarization are strongly linked with age-related long-term deficits in neurological function after stroke. Exp Neurol. 2015; 272:109-19. PMC: 4591088. DOI: 10.1016/j.expneurol.2015.03.021. View

Li Q, Barres B . Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol. 2017; 18(4):225-242. DOI: 10.1038/nri.2017.125. View

10.

Mifflin L, Ofengeim D, Yuan J . Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target. Nat Rev Drug Discov. 2020; 19(8):553-571. PMC: 7362612. DOI: 10.1038/s41573-020-0071-y. View

11.

Boyette-Davis J, Fuchs P . Differential effects of paclitaxel treatment on cognitive functioning and mechanical sensitivity. Neurosci Lett. 2009; 453(3):170-4. DOI: 10.1016/j.neulet.2009.02.031. View

12.

Fischer R, Maier O . Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev. 2015; 2015:610813. PMC: 4365363. DOI: 10.1155/2015/610813. View

13.

You Z, Zhang S, Shen S, Yang J, Ding W, Yang L . Cognitive impairment in a rat model of neuropathic pain: role of hippocampal microtubule stability. Pain. 2018; 159(8):1518-1528. PMC: 6053326. DOI: 10.1097/j.pain.0000000000001233. View

14.

Re D, Le Verche V, Yu C, Amoroso M, Politi K, Phani S . Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron. 2014; 81(5):1001-1008. PMC: 3951532. DOI: 10.1016/j.neuron.2014.01.011. View

15.

Han S, Park J, Mook-Jung I . Amyloid β-interacting partners in Alzheimer's disease: From accomplices to possible therapeutic targets. Prog Neurobiol. 2016; 137:17-38. DOI: 10.1016/j.pneurobio.2015.12.004. View

16.

Laye S, Gheusi G, Cremona S, Combe C, Kelley K, Dantzer R . Endogenous brain IL-1 mediates LPS-induced anorexia and hypothalamic cytokine expression. Am J Physiol Regul Integr Comp Physiol. 2000; 279(1):R93-8. DOI: 10.1152/ajpregu.2000.279.1.R93. View

17.

Bolanos J, Almeida A, Stewart V, Peuchen S, Land J, Clark J . Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem. 1997; 68(6):2227-40. DOI: 10.1046/j.1471-4159.1997.68062227.x. View

18.

He S, Wang L, Miao L, Wang T, Du F, Zhao L . Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009; 137(6):1100-11. DOI: 10.1016/j.cell.2009.05.021. View

19.

Tannock I, Ahles T, Ganz P, van Dam F . Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J Clin Oncol. 2004; 22(11):2233-9. DOI: 10.1200/JCO.2004.08.094. View

20.

Finke C, Pruss H, Heine J, Reuter S, Kopp U, Wegner F . Evaluation of Cognitive Deficits and Structural Hippocampal Damage in Encephalitis With Leucine-Rich, Glioma-Inactivated 1 Antibodies. JAMA Neurol. 2016; 74(1):50-59. DOI: 10.1001/jamaneurol.2016.4226. View