Abstract
Isorhynchophylline (IRN) and rhynchophylline (RN), a pair of stereoisomers, are tetracyclic oxindole alkaloids isolated from Uncaria rhynchophylla, a commonly used Chinese medicinal herb. These two compounds have drawn extensive attention due to their potent neuroprotective effects with promising therapeutic potential for the treatment of Alzheimer's disease (AD). However, IRN and RN can interconvert into each other in vivo after oral administration. The present study aimed to elucidate the pharmacokinetic profiles and disposition kinetics of the administered and generated stereoisomers in the brain and cerebrospinal fluid (CSF) after oral administration of equal dose of IRN or RN to rats. Our study demonstrated that after oral administration, RN showed significantly higher systemic exposure (6.5 folds of IRN, p < 0.001) and disposition in the brain (2.5 folds of IRN, p < 0.01) and CSF (3 folds of IRN, p < 0.001) than IRN. The results indicated that interconversion between IRN and RN occurred. Notably, regardless of the orally administered IRN or RN, RN would always be one of the major or predominant forms present in the body. Our results provided sound evidence supporting further development of RN as a potential therapeutic agent for the treatment of AD. Moreover, the present study sets a solid example that integrating pharmacokinetics is crucial to identify the truly therapeutic agent.
Highlights
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease in the elderly population [1, 2]
The typical multiple reaction monitoring (MRM) chromatograms of the blank biological specimen, blank biological specimen spiked with both analytes and samples obtained after oral administration of IRN or RN were shown in the supplementary data
The MRM chromatograms of blank plasma, brain tissues, and cerebrospinal fluid (CSF) (Figure S1) did not show any interfering peaks or signal at the retention times of the target analytes IRN (4.59 min) and RN (5.44 min)
Summary
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease in the elderly population [1, 2]. Alkaloids-containing herbal extracts have been widely used as therapeutic agents in traditional medicine for thousands of years [3]. Uncaria rhynchophylla (Gou-Teng in Chinese) has been demonstrated as a promising herbal medicine for the treatment of AD. The extract of U. rhynchophylla has been reported to have potent antiaggregation effects on amyloidβ proteins [6] and was demonstrated to improve cognitive deficits induced by D-galactose in mice [7]. The major active components in U. rhynchophylla have been revealed to be oxindole alkaloids. Isorhynchophylline (IRN) and rhynchophylline (RN) (Figure 1) are tetracyclic oxindole alkaloids accounting for more than 43% of the total alkaloid content in U. rhynchophylla [8] and have been regarded as the major pharmacologically active components in the Evidence-Based Complementary and Alternative Medicine
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