Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models
Increasing metabolic syndromes including type-2 diabetes mellitus, obesity, and steatohepatitis are serious problems in most countries in the world. Neurodegenerative diseases such as Alzheimer, Parkinson’s, and Huntington’s diseases are increasing in many countries. However, therapy for these diseases is not sufficient yet. Thus, effective chemotherapy for these diseases is being expected. Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla and related plants. It was found to induce beta-cell differentiation in the precursor pancreatic cells. Oral administration of this compound ameliorated type-2 diabetes mellitus model in mice and rats. Later, fibrosis of the pancreatic islets was found to be greatly reduced by conophylline in the pancreatic islets. It also inhibited chemically induced liver cirrhosis. Further study indicated that conophylline inhibited non-alcoholic steatohepatitis in the model mice. On the one hand, loss of autophagy often causes protein aggregation to give neural cell death. Conophylline was found to activate autophagy in cultured neural cells. Activation of autophagy ameliorated cellular models of Parkinson’s and Huntington’s diseases. Thus, conophylline is likely to be useful for the development of chemotherapy for metabolic and neurodegenerative diseases.
KeywordsConophylline Diabetes mellitus Fibrosis Non-alcoholic steatohepatitis (NASH) Parkinson’s disease
This work was financially supported in part by JSPS Kakenhi Grant Number 17K01967, the Anti-HBV project fund from Japan Agency for Medical and Research Development (AMED), and the Aichi Medical University Research Unit Fund.
Compliance with ethical standards
Conflict of interest
K. U. belongs to the donated fund laboratory supported by Shenzhen Wanhe Pharmaceutical Co., Ltd, Brunese Co., Ltd, and Meiji Seika Pharma Co., Ltd. M. Y. received lecture fee from Otsuka Pharmaceutical Co., Jansen Pharma Co. and Sumitomo Dainippon Pharm Co., and research funding from Bristol Myers Co. and Abbvie GK. The other authors declare no conflict of interest.
- 3.Umezawa K, Taniguchi T, Toi M, Ohse T, Tsutsumi N, Yamamoto T, et al. Growth inhibition of K-Ras-expressing tumours by a new vinca alkaloid, conophylline, in nude mice. Drugs Exptl Clin Res. 1996;22:35–40.Google Scholar
- 18.Sahai A, Malladi P, Pan X, Paul R, Melin-Aldana H, Green RM, et al. Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am J Physiol Gastrointest Liver Physiol. 2004;287(5):G1035–43.CrossRefPubMedGoogle Scholar
- 34.Koide N, Kondo Y, Odkhuu E, Ulziisaikhan J, Ukaji T, Yokochi T, et al. Inhibition of receptor activator of nuclear factor-κB ligand (RANKL) or lipopolysaccharide-induced osteoclast formation by conophylline (CNP) through downregulation of CREB. Immunol Lett. 2014;161:31–7.CrossRefPubMedGoogle Scholar