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-γ-cyclodextrin 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 H2O2-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.
Highlights
Crocetin (CRT) has shown various neuroprotective effects such as antioxidant activities and the inhibition of amyloid β fibril formation, and is a potential therapeutic candidate for Alzheimer’s disease (AD)
When comparing the effects of CRT-γ-CD and CRT on the level of amyloid β (Aβ), the ability of single CRT to inhibit the production of Aβ were not as obvious as that of the inclusion complex. These findings prove that the CRT-γ-CD inclusion complex was able to downregulate CTFs expression and lower the Aβ level, which are pathological hallmarks of AD
Our results showed that both CRT and CRT-γ-CD inclusion complex could protect SH-SY5Y cells from H2O2-induced neurotoxicity in a dose-dependent manner when SH-SY5Y cells were treated with 360 μM of H2O2 (IC50)
Summary
Crocetin (CRT) has shown various neuroprotective effects such as antioxidant activities and the inhibition of amyloid β fibril formation, and is a potential therapeutic candidate for Alzheimer’s disease (AD). 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 H2O2-induced toxicity. 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. This study provides a strategy to deliver CRT across the BBB and gives insight into further pharmaceutical research on CRT for AD treatment It sheds light on brain delivery of other similar drugs by employing γ-CDs
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