Delivering Crocetin across the Blood-Brain Barrier by Using γ-Cyclodextrin to Treat Alzheimer’s Disease

Abstract

Crocetin (CRT) has shown various neuroprotective effects such as antioxidant activities and the inhibition of amyloid β fibril formation, and thus is a potential therapeutic candidate for Alzheimer's disease (AD). However, poor water solubility and bioavailability are the major obstacles in formulation development and pharmaceutical applications of cRt. in this study, a novel water-soluble cRt-γcyclodextrin inclusion complex suitable for intravenous injection was developed. the inclusion complex was nontoxic to normal neuroblastoma cells (N2a cells and SH-SY5Y cells) and AD model cells (7PA2 cells). furthermore, it showed stronger ability to downregulate the expression of c-terminus fragments and level of amyloid β in 7PA2 cell line as compared to the CRT free drug. Both inclusion complex and CRT were able to prevent SH-SY5Y cell death from H 2 o 2-induced toxicity. the pharmacokinetics and biodistribution studies showed that cRt-γ-cyclodextrin inclusion complex significantly increased the bioavailability of cRt and facilitated cRt crossing the blood-brain barrier to enter the brain. this data shows a water-soluble γ-cyclodextrin inclusion complex helped to deliver cRt across the blood-brain barrier. this success should fuel further pharmaceutical research on cRt in the treatment for AD, and it should engender research on γ-cyclodextrin with other drugs that have so far not been explored. Alzheimer's disease (AD) is an irreversible neurodegenerative disease which cannot be cured by any therapeutic approaches up to now 1. As the number of AD patients increases, the need to develop safe, effective drugs for AD therapy becomes increasingly urgent. In traditional herbal medicine, several plants have been used to treat the symptoms of neurodegenerative diseases 2,3. Crocetin (CRT) is an active compound isolated from the fruits of gardenia (Gardenia jasminoides Ellis) and the stigmas of saffron (Crocus sativus L.) 4. Various pharmacological activities of CRT have been reported. CRT can inhibit amyloid β (Aβ) fibril formation, destabilize pre-formed Aβ fibrils and improve Aβ degradation in vitro 5,6. CRT can also reduce Aβ 1-42-induced neurotoxicity by attenuating oxidative stress in murine hippocampal cells 7. Furthermore, CRT can reduce the production of various neurotoxic molecules from neuron, such as lipopolysaccharide (LPS)-induced nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and reactive oxygen species (ROS), which provided strong protection from neuronal cell death 8,9. Moreover, CRT has been proven to cross the blood-brain barrier (BBB) limitedly after administration 10. The mentioned properties of CRT indicate that it may be a potentially useful candidate for AD treatment. In terms of its chemical structure (Fig. 1A), CRT contains two carboxylic acid groups at each end of a polyene chain. However, CRT is insoluble in water in the physiological range (0.0056 g/L); it can only slightly dissolve in pyridine, dimethyl sulfoxide or aqueous alkali solutions at pH above 9 11. Poor solub...

PLGA Multiplex Membrane Platform for Disease Modelling and Testing of Therapeutic Compounds

“…A more quantitative estimation of the neuroprotective effect of trans-crocetin against H 2 O 2 damage is provided by a viability test of the increasing concentration of trans-crocetin ( Figure 3b). In agreement with previous reports [17,18], the investigation evidenced that this natural molecule is able to counteract H 2 O 2 neurotoxicity, preserving cell viability. As expected, oxidative stress due to treatment with H 2 O 2 caused a significant decrease of cell viability of 48% ± 3%.…”

“…Within the scenario of new molecules able to reverse neurodegeneration, emerging paths include the use of natural compounds with promising therapeutic potential. To this purpose, insulted neurons were treated with different concentrations of carotenoid trans-crocetin, which has several pharmacological properties [16][17][18][19]. Nevertheless, its neuroprotective role in counteracting neurodegeneration is poorly understood and requires further investigation.…”

Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes

“…CD-based materials are attractive for biomedical use due to being highly biocompatible, demonstrating low toxicity and immunogenicity in long-term release applications [35,36]. Specific to our current study, CD has been used for neuronal applications with no associated neurotoxicity [37][38][39]. In fact, CDs have been found to be a neuroprotectant and reduce neurotoxicity [37][38][39].…”

Protective Effects of Crocetin against Radiation-Induced Injury in Intestinal Epithelial Cells

“…This problem may be solved with cyclodextrins or similar molecules. For example, Wong et al suggested that crocetin- γ -cyclodextrin inclusion complex could enhance the solubility, bioavailability, and applicability of crocetin [ 33 ]. Puglia et al showed that solid lipid nanoparticles containing crocetin improved its solubility, stability, and pharmacokinetic properties, offering an appropriated approach to resolve this issue [ 34 ].…”