title: Ambient mass spectrometry imaging metabolomics method provides novel insights into the action mechanism of drug candidates.
abstract: Elucidation of the mechanism of action for drug candidates is fundamental to drug development, and it is strongly facilitated by metabolomics. Herein, we developed an imaging metabolomics method based on air-flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) under ambient conditions. This method was subsequently applied to simultaneously profile a novel anti-insomnia drug candidate, N(6)-(4-hydroxybenzyl)-adenosine (NHBA), and various endogenous metabolites in rat whole-body tissue sections after the administration of NHBA. The principal component analysis (PCA) represented by an intuitive color-coding scheme based on hyperspectral imaging revealed in situ molecular profiling alterations in response to stimulation of NHBA, which are in a very low intensity and hidden in massive interferential peaks. We found that the abundance of six endogenous metabolites changed after drug administration. The spatiotemporal distribution indicated that five altered molecules—including neurotransmitter γ-aminobutyric acid, neurotransmitter precursors choline and glycerophosphocholine, energy metabolism-related molecules adenosine (an endogenous sleep factor), and creatine—are closely associated with insomnia or other neurological disorders. These findings not only provide insights into a deep understanding on the mechanism of action of NHBA, but also demonstrate that the AFADESI-MSI-based imaging metabolomics is a powerful technique to investigate the molecular mechanism of drug action, especially for drug candidates with multitarget or undefined target in the preclinical study stage.
authors: †State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Jingjing
authors: J
authors: He
authors: †State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Zhigang
authors: Z
authors: Luo
authors: §Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, People's Republic of China.
authors: Lan
authors: L
authors: Huang
authors: †State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Jiuming
authors: J
authors: He
authors: ‡State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instruments and Mechanology, Tsinghua University, Beijing 100084, People's Republic of China.
authors: Yi
authors: Y
authors: Chen
authors: †State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Xianfang
authors: X
authors: Rong
authors: †State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Shaobo
authors: S
authors: Jia
authors: ‡State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instruments and Mechanology, Tsinghua University, Beijing 100084, People's Republic of China.
authors: Fei
authors: F
authors: Tang
authors: ‡State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instruments and Mechanology, Tsinghua University, Beijing 100084, People's Republic of China.
authors: Xiaohao
authors: X
authors: Wang
authors: †State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Ruiping
authors: R
authors: Zhang
authors: †State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Jianjun
authors: J
authors: Zhang
authors: †State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Jiangong
authors: J
authors: Shi
authors: †State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
authors: Zeper
authors: Z
authors: Abliz
mesh_terms: D000241:Adenosine / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D057225:Data Mining; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics / Q000379:methods*; D057054:Molecular Imaging; D025341:Principal Component Analysis; D051381:Rats; D017208:Rats, Wistar; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy
chemical_list: D000241:Adenosine