Crocin Helps Protect against Cerebral Ischemic Reperfusion Injury

by | Aug 11, 2020 | 2019, Botanicals, Brain Health, Stroke

Written by Angeline A. De Leon, Staff Writer. This study suggests that gut microbiota may be responsible for the conversion of crocin to its metabolite crocetin, which protects against brain injury in a rat model of induced stroke.

botanicals - saffronPharmacological treatment options for ischemic stroke, the most common type of stroke involving an obstruction of blood supply to the brain, are quite limited 1. Crocin is one of the main active ingredients in saffron, a spice with notable cardiac-cerebral vascular benefits 2,3, and studies suggest that it may help protect against cerebral ischemic reperfusion injury by attenuating oxidative stress in the brain and increasing antioxidant capacity 4. The metabolite of crocin, crocetin, is thought to be involved in this pharmacological effect, but the exact mechanism of action, including the potential targeting site of crocin, requires further elucidation 5. Epidemiological research has highlighted the correlation between gut microbiota composition and stroke outcome 6, suggesting that such a CVD event is associated with lower abundance of certain bacterial strains 7 and altered permeability of the intestinal mucosal barrier 8. In a 2019 study 9 published in Frontiers in Pharmacology, researchers examined the effects of oral vs. intravenous administration of crocin in a rat model of cerebral ischemic/reperfusion injury (I/R injury).

A group of male Sprague-Dawley rats were divided into two groups, half undergoing transient middle cerebral artery occlusion (MCAO) to induce cerebral I/R injury and the other half receiving a sham operation. All rats then received one of four treatments: an intravenous injection of saline (3 mg/kg), an intravenous injection of Edaravone (free radical scavenger) (3 mg/kg), an intravenous injection of crocin (1 mg/kg) (all injections administered 2 hours after the onset of ischemia), or an oral dose of crocin (60 mg/kg) administered once daily for 4 days prior to and on the day of the MCAO procedure. Brain tissue samples were collected for biochemical assay, measurement of infarct volume (necrotic brain tissue), and metabolomics study. An in vitro metabolic analysis was also carried out involving the addition of 5 µL of crocin or 20 µM of crocetin to 45 µL of fermented gut content of normal rats. Samples were then incubated, extracted, and analyzed to determine concentrations of crocin and crocetin.

Oral administration of crocin was found to be associated with a significant reduction in cerebral infarction volumes in I/R injured rats (p = 0.001) and increased total antioxidant activity of brain tissues in the infarction region (p < 0.05). Analyses measuring metabolic disturbances in injured brain regions also indicated greater similarity in metabolomic composition between the sham group and I/R injured rats receiving oral administration of crocin, suggesting crocin’s amelioration of dysfunctional metabolism in the brain associated with I/R injury. Following oral administration of crocin, I/R injured rats did not show significant traces of either crocin or crocetin in cerebral tissue. In vitro measurement of the metabolism of crocin by gut flora revealed that orally administered crocin was poorly absorbed by enterocytes (intestinal absorptive cells) and that a large portion of it remained in the gut where it was metabolized into crocetin by gut flora.

In vivo and in vitro evidence from the study confirms the cerebral-protective effects of orally administered crocin in a rodent model of cerebral I/R injury. Compared to intravenous delivery, oral intake of crocin significantly reduced cerebral infarction volumes, increased antioxidant activity, and attenuated metabolic disturbance of the brain caused by I/R injury. Findings also suggest that gut microbiota may play a key role in activating the pharmacological effects of crocin. Neither crocin nor crocetin appeared capable of crossing the blood-brain barrier and while orally administered crocin was poorly absorbed by gut flora, residual traces of it were directly metabolized into crocetin by gut microbiota, suggesting that the gut microbiome may be the targeting site associated with crocin’s cerebral-protective effects. Overall, findings confirm the cardiac-cerebral vascular benefits of orally administered crocin, highlighting the crucial role of gut microbiota in its therapeutic effects. Additional studies using human models of I/R injury are warranted for the future.

Source: Zhang Y, Geng J, Hong Y, et al. Orally administered crocin protects against cerebral ischemia/reperfusion injury through the metabolic transformation of crocetin by gut microbiota. Frontiers in Pharmacology. 2019; 10: 440. DOI: 10.3389/fphar.2019.0040.

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Posted August 11, 2020.

Angeline A. De Leon, MA, graduated from the University of Illinois at Urbana-Champaign in 2010, completing a bachelor’s degree in psychology, with a concentration in neuroscience. She received her master’s degree from The Ohio State University in 2013, where she studied clinical neuroscience within an integrative health program. Her specialized area of research involves the complementary use of neuroimaging and neuropsychology-based methodologies to examine how lifestyle factors, such as physical activity and meditation, can influence brain plasticity and enhance overall connectivity.

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