Arginine Biosynthesis Pathway Found to Play a Key Role in the Neuroprotective Effect of Liu-Wei-Luo-Bi (LWLB) Granules in Diabetic db/db Mice with Peripheral Neuropathy Using an Untargeted Metabolomics Strategy

Qiong Liu; Yafei Chen; Bo Wang; Yinying Chen; Bing Li; Shuang Guan; Kehe Du; Xiaoyang Liu; Yanan Yu; Jun Liu; Zhong Wang

doi:10.2147/DMSO.S423388

Arginine Biosynthesis Pathway Found to Play a Key Role in the Neuroprotective Effect of Liu-Wei-Luo-Bi (LWLB) Granules in Diabetic db/db Mice with Peripheral Neuropathy Using an Untargeted Metabolomics Strategy

Diabetes Metab Syndr Obes. 2023 Dec 11:16:4065-4080. doi: 10.2147/DMSO.S423388. eCollection 2023.

Authors

Qiong Liu^{1

2}, Yafei Chen¹, Bo Wang¹, Yinying Chen³, Bing Li⁴, Shuang Guan¹, Kehe Du⁵, Xiaoyang Liu⁵, Yanan Yu¹, Jun Liu¹, Zhong Wang¹

Affiliations

¹ Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China.
² Postdoctoral Research Station, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China.
³ Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China.
⁴ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People's Republic of China.
⁵ iPhase Pharma Services, Beijing, People's Republic of China.

Abstract

Aim: Liu-Wei-Luo-Bi (LWLB) granules was a Chinese compound prescription for treating diabetic peripheral neuropathy (DPN). The aim of this study was to investigate the effect of LWLB granules on diabetic mice with peripheral neuropathy and to elucidate the potential mechanism based on an untargeted metabolomics approach.

Methods: One hundred forty db/db mice were randomly divided into seven groups: the Control group, DPN group, Mudan (MD) granules group, Epalrestat (Epa) group, and the LWLB low, medium, or high dose (LW-l, LW-m, or LW-h) group. After 12 weeks of treatment, body weight, blood glucose, mechanical pain threshold, motor conduction velocity (MCV), sensory conduction velocity (SCV), and Pathological Organization of the Sciatic and Caudal Nerves in mice were measured. Serum samples were collected for untargeted metabolomics analysis using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and multivariate statistics. Disease-related pathways were screened out with function enrichment analyses of candidate biomarkers.

Results: LWLB granules can improve the peripheral neuropathy of type 2 diabetic mice with peripheral nerve conduction disorders, mainly through significantly improving the nerve conduction velocity (P < 0.05) and lowering the mechanical pain threshold (P < 0.05). A total of 43 metabolites were identified as potential biomarkers related to the therapeutic effect of LWLB granules. Fifty, 4, and 26; 23, 4, and 22; and 24, 1, and 16 biomarkers were discovered in the LW-l, LW-m, and LW-h groups at the 4th, 6th, and 12th weeks, respectively. Five, three, seven, five, and four metabolic pathways were found in MD, Epa, LW-l, LW-m, and LW-h groups, respectively. The arginine biosynthesis pathway is the overlapping pathway in LW-l, LW-m, and LW-h groups.

Conclusion: LWLB granules have an obvious neuroprotective effect on diabetic peripheral neuropathy, and the metabolism mechanism of LWLB is mainly related to the arginine biosynthesis pathway on diabetic db/db mice with peripheral neuropathy.

Keywords: Liu-Wei-Luo-Bi granules; Traditional Chinese Medicine; arginine biosynthesis; diabetic peripheral neuropathy; untargeted metabolomics.

Grants and funding

This study was supported by the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (2017ZX09301‐059), National Natural Science Foundation of China (81230086) and the Fundamental Research Funds for the Central public welfare research institutes (ZZ0908029).