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Quantitative Proteomics Characterization of the Effect and Mechanism of Trichostatin A on the Hippocampus of Type II Diabetic Mice

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Abstract

Diabetic encephalopathy (DE) is one of the complications of diabetes mellitus with mild-to-moderate cognitive impairment. Trichostatin A (TSA) has been revealed to show protective effect on central nervous systems in Alzheimer’s disease (AD) and hypoxic–ischemic brain injury. However, the effect and molecular mechanism of TSA on cognitive function of DE are unknown. Here, we demonstrated that cognitive function was damaged in diabetic mice versus normal mice and treatment with TSA improved cognitive function in diabetic mice. Proteomic analysis of the hippocampus revealed 174 differentially expressed proteins in diabetic mice compared with normal mice. TSA treatment reversed the expression levels of 111 differentially expressed proteins grouped into functional clusters, including the longevity regulating pathway, the insulin signaling pathway, peroxisomes, protein processing in the endoplasmic reticulum, and ribosomes. Furthermore, protein–protein interaction network analysis of TSA-reversed proteins revealed that UBA52, CAT, RPL29, RPL35A, CANX, RPL37, and PRKAA2 were the main hub proteins. Multiple KEGG pathway-enriched CAT and PRKAA2 levels were significantly decreased in the hippocampus of diabetic mice versus normal mice, which was reversed by TSA administration. Finally, screening for potential similar or ancillary drugs for TSA treatment indicated that HDAC inhibitors ISOX, apicidin, and panobinostat were the most promising similar drugs, and the PI3K inhibitor GSK-1059615, the Aurora kinase inhibitor alisertib, and the nucleophosmin inhibitor avrainvillamide-analog-6 were the most promising ancillary drugs. In conclusion, our study revealed that CAT and PRKAA2 were the key proteins involved in the improvement of DE after TSA treatment. ISOX, apicidin, and panobinostat were promising similar drugs and that GSK-1059615, alisertib, and avrainvillamide-analog-6 were promising ancillary drugs to TSA in the treatment of DE.

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Data Availability

All data of the present study are available upon request from the corresponding author. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (Sun et al. 2022) partner repository with the dataset identifier PXD036588.

Abbreviations

DE:

Diabetic encephalopathy

TSA:

Trichostatin A

T2DM:

Type II diabetes mellitus

HDAC:

Histone deacetylase

AD:

Alzheimer’s disease

PCA:

Principal component analysis

CAT:

Catalase

PRKAA2:

Protein kinase AMP-activated catalytic subunit alpha 2

rRNA:

Ribosomal RNA

APP:

Beta-amyloid precursor protein

IR:

Insulin receptor

IRS:

Insulin receptor substrates

MWM:

Morris water maze

HE:

Hematoxylin and eosin

PPI:

Protein–protein interaction

IOD:

Integrated optical density

BSA:

Bovine serum albumin

ECL:

Enhanced chemiluminescence

CMap:

Connectivity Map

ANOVA:

One-way Analysis of Variance

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Funding

This research was supported by Grants from the National Natural Science Foundation of China (No. 82171365) and the Natural Science Foundation of Hebei Province (H2021206086, H2021206098).

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Author notes

  1. Wandi Wei and Qingning Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China

    Wandi Wei, Tingting Jin, Jialing Zhao, Fan Li, Song Zhao & Jun Hao

  2. Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China

    Wandi Wei, Tingting Jin, Jialing Zhao, Fan Li, Song Zhao & Jun Hao

  3. Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, 050017, Hebei, China

    Qingning Zhang & Dezhi Kong

  4. Department of Electromyogram, The Third Hospital of Hebei Medical University, Shijiazhuang, China

    Lin Zhu

  5. Hebei Key Laboratory of Forensic Medicine, Shijiazhuang, China

    Fan Li & Jun Hao

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  1. Wandi Wei
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  2. Qingning Zhang
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Contributions

WW, QZ, DK, and JH conceived and designed the experiment; WW, QZ, TJ, LZ, and JZ performed the experiments; WW, QZ, FL, SZ, DK, and JL analyzed the data; DK and JH wrote the manuscript.

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Correspondence to Dezhi Kong or Jun Hao.

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Wei, W., Zhang, Q., Jin, T. et al. Quantitative Proteomics Characterization of the Effect and Mechanism of Trichostatin A on the Hippocampus of Type II Diabetic Mice. Cell Mol Neurobiol 43, 4309–4332 (2023). https://doi.org/10.1007/s10571-023-01424-7

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