Oren-gedoku-to and its Constituents with Therapeutic Potential in Alzheimer's Disease Inhibit Indoleamine 2, 3-Dioxygenase Activity In Vitro

Abstract

A well-known traditional Chinese medicinal prescription, Oren-gedoku-to (OGT), has been used in clinical therapies for many types of dementia in China and Japan. Additionally, it ameliorates the age-related deterioration of learning and memory in an Alzheimer's disease (AD) rat model. Indoleamine 2, 3-dioxygenase (IDO-1) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism, which ultimately leads to the production of the excitotoxin quinolinic acid (QUIN). IDO-1 has recently been established as one of the key players involved in the pathogenesis of AD. OGT is indicated to prevent cholinergic dysfunction and reduce oxidative stress; however, the exact mechanism underlying its ability to improve cognitive ability remains elusive. Here we present a novel mechanism of OGT's therapeutic potential in AD. We demonstrated that OGT significantly inhibited recombinant human IDO-1 (rhIDO-1) activity in vitro, and its four main constituents (i.e., berberine, palmatine, jatrorrhizine, and baicalein) were potent IDO-1 inhibitors. IC50 values, obtained from a cell-based assay, of HEK 293 cells and an enzymatic assay were much lower than the most commonly used IDO-1 inhibitor, 1-methyl tryptophan (1-MT). Berberine was the best inhibitor and had IC50 values of 7 μM (cell-based assay) and 9.3 μM (enzymatic assay). Jatrorrhizine and palmatine exhibited irreversible inhibition of rhIDO-1, whereas berberine and baicalein behaved as uncompetitive, reversible inhibitors with Ki values of 8 μM and 215 μM, respectively. In conclusion, constituents of OGT show strong IDO-1 inhibitory activity and may have significant therapeutic potential for AD.

The kynurenine pathway and neurodegenerative disease

“…Further evidence supporting the neuroprotective potential of TDO/IDO inhibition has been observed with the compound coptisine -the main active component of the Chinese prescription medication Oren-gedoku-to (OGT) -which is a potent inhibitor of IDO1 [92]. Indeed, treatment of an AD mammalian cell model with coptisine A increased viability while reversing the raised activity of IDO1.…”

Berberine Prolongs Life Span and Stimulates Locomotor Activity of <i>Drosophila melanogaster</i>

“…Both inhibitors are not available for human use. Berberine, isoquinoline alkaloid isolated from Berberis aristata , a major herb widely used in Indian and Chinese systems of medicine, is a strong inhibitor of the rate-limiting enzyme of TRP-KYN metabolism [7]. We suggested that berberine (as an inhibitor of KYN formation from TRP) might prolong the life span.…”

Inhibition of eukaryotic elongation factor-2 confers to tumor suppression by a herbal formulation Huanglian-Jiedu decoction in human hepatocellular carcinoma

“…It is also found to reduce neutrophil infiltration (Hwang et al, 2002) and suppress preadipocyte differentiation (Ikarashi et al, 2012). These actions rendered possibility of the decoction in treating various diseases including acute gastric mucosal lesions, liver injury, colitis, hypercholesterolemia, transient cerebral ischemia, allergic dermatitis and Alzheimer's disease (Gao et al, 2005;Ohta et al, 1999;Ohta et al, 1997;Sekiya et al, 2005;Xu et al, 2000;Yu et al, 2010;Zhou and Mineshita, 1999). Our clinical observation and review studies also showed that HJLDD has liver protection and anticancer effects and therefore possesses high potential in treatment of liver diseases and cancer (Feng et al, 2008;Tang et al, 2009).…”