Integrated transcriptome and metabolome analysis to investigate the mechanism of intranasal insulin treatment in a rat model of vascular dementia

Liang Tang; Yan Wang; Xujing Gong; Ju Xiang; Yan Zhang; Qin Xiang; Jianming Li

doi:10.3389/fphar.2023.1182803

Integrated transcriptome and metabolome analysis to investigate the mechanism of intranasal insulin treatment in a rat model of vascular dementia

Front Pharmacol. 2023 May 15:14:1182803. doi: 10.3389/fphar.2023.1182803. eCollection 2023.

Authors

Liang Tang^{1

2

3}, Yan Wang¹, Xujing Gong¹, Ju Xiang^{1

2

3

4}, Yan Zhang^{1

3

5}, Qin Xiang^{1

2

3}, Jianming Li^{1

2

3}

Affiliations

¹ Department of Basic Biology, Changsha Medical College, Changsha, China.
² Center for Neuroscience and Behavior, Changsha Medical College, Changsha, China.
³ The Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, Changsha Medical College, Changsha, China.
⁴ School of Computer and Communication Engineering, Changsha University of Science and Technology, Changsha, China.
⁵ School of Computer Science and Engineering, Central South University, Changsha, China.

Abstract

Introduction: Insulin has an effect on neurodegenerative diseases. However, the role and mechanism of insulin in vascular dementia (VD) and its underlying mechanism are unknown. In this study, we aimed to investigate the effects and mechanism of insulin on VD. Methods: Experimental rats were randomly assigned to control (CK), Sham, VD, and insulin (INS) + VD groups. Insulin was administered by intranasal spray. Cognitive function was evaluated using the Morris's water maze. Nissl's staining and immunohistochemical staining were used to assess morphological alterations. Apoptosis was evaluated using TUNEL-staining. Transcriptome and metabolome analyses were performed to identify differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs), respectively. Results: Insulin significantly improved cognitive and memory functions in VD model rats (p < 0.05). Compared with the VD group, the insulin + VD group exhibited significantly reduced the number of Nissl's bodies numbers, apoptosis level, GFAP-positive cell numbers, apoptosis rates, and p-tau and tau levels in the hippocampal CA1 region (p < 0.05). Transcriptomic analysis found 1,257 and 938 DEGs in the VD vs. CK and insulin + VD vs. VD comparisons, respectively. The DEGs were mainly enriched in calcium signaling, cAMP signaling, axon guidance, and glutamatergic synapse signaling pathways. In addition, metabolomic analysis identified 1 and 14 DEMs between groups in negative and positive modes, respectively. KEGG pathway analysis indicated that DEGs and DEMs were mostly enriched in metabolic pathway. Conclusion: Insulin could effectively improve cognitive function in VD model rats by downregulating tau and p-tau expression, inhibiting astrocyte inflammation and neuron apoptosis, and regulating genes involved in calcium signaling, cAMP signaling, axon guidance, and glutamatergic synapse pathways, as well as metabolites involved in metabolic pathway.

Keywords: hippocampus; insulin; integrated analysis; multi-omics; vascular dementia.

Grants and funding

This work was supported by the Changsha Outstanding Innovative Young People Training Scheme (Grant Nos kq2206058, kq2206056), the Natural Science Foundation of Hunan Province (2021JJ40641), the Foundation of Project of Hunan Health and Family Planning Commission (Grant No. 202202082739), The Foundation of the Education Department of Hunan Province (Grant Nos 21A0586, 22A0662, 22A0656), The “Double-First Class” Application Characteristic Discipline of Hunan Province (Clinical Medicine).