Glabridin is chemically an isoflavane class of natural
phenols
and is found mainly in the roots of
Glycyrrhiza glabra
. It has several beneficial pharmacological actions for the management
of inflammatory disorders as well as can counteract drug-induced toxic
effects. On the other hand, methotrexate (MTX) is the first-line disease-modifying
antirheumatic drug for the treatment of rheumatoid arthritis. However,
its treatment is associated with major side effects like hepatotoxicity.
In the quest to explore a suitable combination therapy that can improve
the efficacy and reduce the hepatotoxicity of MTX, we hypothesized
that glabridin might serve the purpose for which there is no literature
precedent to date. We explored the antiarthritic efficacy of MTX in
the presence or the absence of glabridin using Mycobacterium-induced
arthritic model in rats. The results of reduction in paw swelling,
inhibition of serum cytokines (TNF-α, IL-6, and IL-1β),
and improvement in the bone joints from radiological and histopathological
findings suggest that glabridin can substantially augment the antiarthritic
efficacy of MTX. Further, results of concomitant glabridin treatment
with MTX in the experimental time frame demonstrate that glabridin
could considerably prevent the MTX-induced hepatic alteration in serum
biochemical markers (SGPT and SGOT) and oxidative stress markers (malondialdehyde
(MDA) and glutathione reduced (GSH)). Moreover, glabridin showed a
marked effect in impeding the regulation of NF-κB/IκBα
and Nrf2/Keap1 pathways in the hepatic tissues. The results of simultaneous
administration of glabridin with MTX in the rat model indicate that
glabridin had no pronounced effect of causing severe alteration in
the pharmacokinetic behavior of MTX. In summary, glabridin can significantly
potentiate the antiarthritic efficacy of MTX and can also minimize
its hepatotoxicity
via
the inhibition of inflammation
and oxidative stress. Further research should be performed to develop
glabridin as a phytotherapeutics for the improved efficacy and better
tolerability of MTX at the reduced dose level of MTX.
Pinocembrin, a bioflavonoid,
is extensively used in complementary/alternative
medicine. It turns out as a promising candidate against neurodegenerative
diseases because of its multifaceted pharmacological action toward
neuroprotection. However, literature evidence is still lacking for
its inhibitory action on CYP1A2, which is responsible for xenobiotic
metabolism leading to the generation of toxic metabolites and bioactivation
of procarcinogens. In the present study, our aim was to evaluate the
CYP1A2 inhibitory potential of pinocembrin via
in silico
,
in vitro
, and
in vivo
investigations.
From the results of
in vitro
studies, pinocembrin
is found to be a potent and competitive inhibitor of CYP1A2.
In vitro
–
in vivo
extrapolation results
indicate the potential of pinocembrin to interact with CYP1A2 substrate
drugs clinically. Molecular docking-based
in silico
studies demonstrate the strong interaction of pinocembrin with human
CYP1A2. In
in vivo
investigations using a rat model,
pinocembrin displayed a marked alteration in the plasma exposure of
CYP1A2 substrate drugs, namely, caffeine and tacrine. In conclusion,
pinocembrin has a potent CYP1A2 inhibitory action to cause drug interactions,
and further confirmatory study is warranted at the clinical level.
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