Abstract
Our pilot study suggested that orally administered crocin was hardly absorbed into circulatory system, but it was effective against cerebral ischemic/reperfusion (I/R) injury. The pharmacologically active component and targeting site of crocin remain elusive. In this study, the cerebral-protective effect of crocin was evaluated on a rat transient middle cerebral artery occlusion (MCAO) model. Our data showed that oral administration of crocin had better effectiveness in cerebral protection than an intravenous injection. Neither crocin nor its metabolite crocetin were determined in the brain of cerebral I/R rats, indicating a target site of periphery. Abundant crocetin was detected in plasma after oral administration instead of intravenous injection of crocin. Meanwhile, orally administered crocetin showed similar cerebral protection to that of crocin, but this exciting effect was not clearly observed by intravenous administration of crocetin, indicating the importance of crocetin in gut. Moreover, orally administered crocin showed less cerebral-protective effect in pseudo germ-free (pGF) MCAO rats. In vitro and in vivo experiments confirmed that crocin could be deglycosylated to crocetin in gut content of normal rats, rather than that of pGF rats, indicating that gut microbiota facilitated the transformation of crocin into crocetin, which played a key role in the activation of the pharmacological effect. Metabolomic study revealed that microbial-host co-metabolic molecules were significantly perturbed after oral administration of crocin, indicating a regulation on intestinal ecosystem. It was further suggested that gut microbiota may be the potential target of the cerebral-protective effect of crocin.
Highlights
Stroke is a highly prevalent disease and a major cause of death and disability (Rothwell et al, 2011)
Compared to the model group, oral administration of crocin showed a significant reduction in the cerebral infarction volumes (P = 0.001)
Clear differences were obtained from the orthogonal projection to latent structure-discriminant analysis (OPLS-DA) model when we focused on the model group vs. the sham-operated group for cerebral I/R injury; and the crocin (i.g. administration) group vs. the model group for the crocin treatment
Summary
Stroke is a highly prevalent disease and a major cause of death and disability (Rothwell et al, 2011). There is no alternative oral drug, especially for the patients who have already had ischemic vascular events (Nenci and Goracci, 2000). Considering that the traditional method of saffron intake is oral administration, the water-soluble component, crocin, is supposed to account for the pharmacological activity of saffron. Only trace levels of crocin was found in the systemic circulation after oral administration (Asai et al, 2005; Xi et al, 2007; Lautenschlager et al, 2015), while the system exposure of its metabolite, crocetin, is 56- to 81-fold higher than crocin, suggesting that crocetin may be the active component potentially responsible for the pharmacological effects of crocin (Zhang et al, 2017)
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