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Protective Effects of ACY-1215 Against Chemotherapy-Related Cognitive Impairment and Brain Damage in Mice

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Abstract

Chemotherapy-related cognitive impairment (CRCI) is a potential long-term side effect during cancer treatment. There are currently no effective treatments for CRCI. Reduction or inhibition of histone deacetylase 6 (HDAC6) has been considered a possible therapeutic strategy for cognitive deficits. HDAC6 inhibition recently has been shown to reverse chemotherapy-induced peripheral neuropathy effectively. In the present study, we examined the effect of HDAC6 inhibitor ACY-1215 (Ricolinostat) on cisplatin-induced brain damage and cognitive deficits in mice. Our results showed that ACY-1215 ameliorated behavioral deficits and dendritic spine loss and increased synaptic density in cisplatin-treated mice. Mechanistically, HDAC6 inhibitor ACY-1215 enhanced α-tubulin acetylation in the hippocampus of cisplatin-treated mice. Furthermore, ACY-1215 recovered cisplatin-induced impaired mitochondrial transport and mitochondrial dysfunction in the hippocampus. Our results suggest that inhibition of HDAC6 improves established cisplatin-induced cognitive deficits by the restoration of mitochondrial and synaptic impairments. These results offer prospective approaches for CRCI, especially because ACY1215 currently serves as an add-on cancer therapy during clinical trials.

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Abbreviations

CRCI:

Chemotherapy-related cognitive impairment

HDAC6:

Histone deacetylase 6

MMP:

Mitochondrial membrane potential

mtDNA:

Mitochondria DNA

MWM:

Morris water maze

nDNA:

Nuclear DNA

NOR:

Novel object recognition

ROS:

Reactive oxygen species

PSD95:

Postsynaptic density protein 95

vGlut1:

Vesicular glutamate transporter type 1

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Acknowledgements

The present work was supported by National Natural Science Foundation of China (81601225 and U1804174), Henan Provincial Key Research and Development and Promotion Project (192102310081), Science and Technology Innovation Talents in the Universities of Henan Province (20HASTIT044), Science & Technology Innovation teams in Universities of Henan Province (18IRTSTHN026), Outstanding Youth of Science and Technology Innovation in Henan Province (184100510006), Student Research Training Program of Henan University of Science and Technology (2019314).

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Authors and Affiliations

  1. Medical College, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of China

    Dongmei Wang, Bei Wang, Xiaohui Dong, Yanwei Su & Sanqiang Li

  2. College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, People’s Republic of China

    Yumei Liu

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Fig. S1

Effects of HDAC6 inhibitor ACY-1215 treatment on cisplatin-induced loss of body weight. The percentage of baseline body weight. All data are presented as mean ± S.E.M. (n = 12–14, * p < 0.05, ** p < 0.01, Control mice vs. cisplatin-treated mice; #p < 0.05, ##p < 0.01, ACY-1215 mice vs. Cisplatin/ACY-1215 mice). Electronic supplementary material 1 (TIF 186 kb)

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Wang, D., Wang, B., Liu, Y. et al. Protective Effects of ACY-1215 Against Chemotherapy-Related Cognitive Impairment and Brain Damage in Mice. Neurochem Res 44, 2460–2469 (2019). https://doi.org/10.1007/s11064-019-02882-6

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