Bioavailability Enhancement of Cepharanthine via Pulmonary Administration in Rats and Its Therapeutic Potential for Pulmonary Fibrosis Associated with COVID-19 Infection

Abstract

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-β1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection.

Asiaticoside might attenuate bleomycin‐induced pulmonary fibrosis by activating cAMP and Rap1 signalling pathway assisted by A2AR

“…27 Finally, the sequencing data were aligned to the mouse reference genome (mm10) 28 . The read counts files were filtered with low expression and normalized by the ‘DEseq2’ package 22 …”

“…Asiaticoside (AS) is a triterpenoid saponin purified from the plant Centella asiatica with various biological effects, such as antioxidant, anti‐inflammatory and anti‐hepatofibric effects 18‐20 . Centella asiatica is a traditional Chinese medicine, which is widely used to wound healing and alleviating the symptoms of interstitial lung disease 21,22 . Tang et al found AS could inhibit the proliferation of fibroblasts and the expression of type I and type III collagen protein in the process of wound healing 23 .…”

The brief overview, antivirus and anti-SARS-CoV-2 activity, quantitative methods, and pharmacokinetics of cepharanthine: a potential small-molecule drug against COVID-19

“…CEP has been shown to have multiple molecular mechanisms, including stabilizing cell membrane fluidity ( Matsuda et al, 2014 ), inhibiting drug efflux ( Peng et al, 2012 ; Bailly, 2019 ), scavenging free radicals ( Rogosnitzky and Danks, 2011 ), alleviating inflammatory factor production, inhibiting cytoplasmic nuclear transcription factor (NF-κB) ( Lin et al, 2018 ) and activating the adenosine-activated protein kinase (AMPK) signaling pathway ( Fan et al, 2020 ), inhibiting the integrins/ILK/RACK1/PKCα/NF-κB signaling axis ( Yang et al, 2021 ), and inhibiting receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation and bone-resorbing activities ( Lin et al, 2018 ). These mechanisms have been linked to various biological activities of CEP, such as anti-inflammatory ( Bailly, 2019 ; Rogosnitzky et al, 2020 ), immunomodulatory ( Yamazaki et al, 2017 ; Bailly, 2019 ), anti-osteoporotic ( Zhou et al, 2018 ; Yao et al, 2022 ), antioxidant ( Bailly, 2019 ), inhibition of drug efflux transporters ( Peng et al, 2012 ; Kathawala et al, 2014 ), exerting protective effects against pulmonary fibrosis ( Li et al, 2022 ), anticancer ( Tang et al, 2018 ; Bailly, 2019 ; Rogosnitzky et al, 2020 ; Wang et al, 2020 ), and anti-parasitic effects ( Bailly, 2019 ). A historical overview of the research and development of CEP, which traces its main clinical applications and biochemical characteristics from 1934 to 2018, is presented in Figure 2 ( Bailly, 2019 ).…”

Cepharanthine Ameliorates Pulmonary Fibrosis by Inhibiting the NF-κB/NLRP3 Pathway, Fibroblast-to-Myofibroblast Transition and Inflammation

“…From a chemical perspective, CEP is also known as 12-O-methyl cepharanoline [ 24 ] and exhibits multiple pharmacological properties, including anti-inflammatory [ 25 ], immuno-regulatory [ 26 ], anticancer [ 27 ], and antiviral properties [ 28 , 29 , 30 ]. In a previous study, we found that CEP significantly reduced bleomycin (BLM)-induced collagen accumulation and inflammatory responses, engendering a protective effect against PF [ 31 ]. However, to the best of our knowledge, no studies have reported the underlying action mechanism of CEP in treatment against PF.…”