Catalpol in Diabetes and its Complications: A Review of Pharmacology, Pharmacokinetics, and Safety

Abstract

This review aimed to provide a general view of catalpol in protection against diabetes and diabetic complications, as well as its pharmacokinetics and safety concerns. The following databases were consulted with the retrieval of more than 100 publications through June 2019: PubMed, Chinese National Knowledge Infrastructure, WanFang Data, and web of science. Catalpol exerts an anti-diabetic effect in different animal models with an oral dosage ranging from 2.5 to 200 mg/kg in rats and 10 to 200 mg/kg in mice. Besides, catalpol may prevent the development of diabetic complications in kidney, heart, central nervous system, and bone. The underlying mechanism may be associated with an inhibition of inflammation, oxidative stress, and apoptosis through modulation of various cellular signaling, such as AMPK/PI3K/Akt, PPAR/ACC, JNK/NF-κB, and AGE/RAGE/NOX4 signaling pathways, as well as PKCγ and Cav-1 expression. The pharmacokinetic profile reveals that catalpol could pass the blood-brain barrier and has a potential to be orally administrated. Taken together, catalpol is a well-tolerated natural compound with promising pharmacological actions in protection against diabetes and diabetic complications via multi-targets, offering a novel scaffold for the development of anti-diabetic drug candidate. Further prospective and well-designed clinical trials will shed light on the potential of clinical usage of catalpol.

Keywords: catalpol; diabetes; diabetic complications; pharmacokinetic; pharmacology; safety.

Figure 1

Rehmannia glutinosa, Catalpol, and its chemical structure. (A) Rehmannia glutinosa, (B) Shengdi (dry roots of Rehmannia glutinosa), (C,D) Crystallized powder of catalpol, (E) Chemical structure of catalpol. The International Union of Pure and Applied Chemistry (IUPAC) name of catalpol: (3R,4S,5S,6R)-2-[[(1S,2S,4S,5S,6R,10S)-5-hydroxy-2-(hydroxymethyl)-3,9-dioxatricyclo[4.4.0.02,4]dec-7-en-10-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol.

Figure 2

The relevant molecular targets of diabetic liver disorder modulated by catalpol. Catalpol is actively involved in improving glucose and lipid metabolism, ameliorating oxidative stress, and restoring mitochondrial function. Abbreviations: Acot1: acyl-CoA thioesterase 1, ACC: acetyl-CoA carboxylase, AMPK: adenosine 5‘-monophosphate-activated protein kinase, Akt: protein kinase B, Cyp46a1: cytochrome P450-family 46-subfamily a-polypeptide 1, Drp1: dynamin-related protein 1, Fabp5: fatty acid-binding protein 5, Fis1: fission 1, FOXO1: forkhead box protein O1, G6pase: Glucose-6-phosphatase, G6pd2: glucose-6-phosphate dehydrogenase 2, GLUT4: glucose transporter type 4, GSK3β: glycogen synthase kinase 3β, GSH-Px: glutathione peroxidase, HMGCR: hydroxymethyl glutaric acid acyl CoA, Idh2: isocitrate dehydrogenase 2, IRS1: insulin receptor substrate 1, Lipg: lipase, MDA: malonaldehyde, Mfn1: mitofusin-1, NOX4: NADPH oxidase 4, PEPCK: phosphoenolpyruvate carboxykinase, PI3K: phosphatidylinositol (−3) kinase, ROS: reactive oxygen species, SOCS3: suppressor of cytokine signaling 3, T-SOD: total superoxide dismutase.

Figure 3

Catalpol regulates various genes and proteins of pancreatic, skeletal, and adipose tissue in the management of diabetes. Abbreviations: CAT: Catalase, IKKβ: inhibitory kappa B kinase, MHC: myosin heavy chain, JNK: c-Jun N-terminal kinase, MCP-1: Monocyte chemokine-1, MyoD: myogenic differentiation, MyoG: myogenin, NF-κB: nuclear factor-κB, PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PPARγ: peroxisome proliferators-activated receptor-γ, RAGE: receptor for advanced glycation end product, TNF-α: Tumor necrosis factor-alpha.

Figure 4

Catalpol alleviates renal damage through improving lipid metabolism, IGF-1 signaling, and inhibiting mesangial cell proliferation. Abbreviations: IGF: insulin-like growth factor, IGFR: insulin-like growth factor receptor.

Figure 5

The relevant molecular targets of diabetic complications modulated by catalpol. Abbreviations: ALP: alkaline phosphatase, Cav-1: caveolin-1, ET-1: endothelin-1, HDAC4: histone deacetylase 4, IκB-α: NF-κB inhibitor-α, LDH: lactate dehydrogenase, MAPK: mitogen-activated protein kinase, mTOR: mammalian target of rapamycin, NEAT1: nuclear paraspeckle assembly transcript 1, NGF: nerve Growth Factor, NIP: neointimal proliferation, OPN: osteopontin, PCG: protein carbonyl groups, PKCγ: protein kinase C-gamma, TGF-β: transforming growth factor-beta, VCAM-1: vascular cell adhesion molecule-1.

Figure 6

Catalpol reduces diabetic complications and disorders in different systems and/or tissues, including liver, pancreas, adipose tissue, skeletal muscle, bone, kidney, cardiovascular system, and central and peripheral nervous system.