Cyclodextrin-enabled δ-Tocotrienol for Treating Stress and Memory Dysfunction: Molecular Insights, Biotechnological Applications and Biomanufacturing Implications.

Abstract

Background: Antioxidants possess substantial health benefits owing to their ability to alleviate cellular oxidative stress, reactive oxygen species generation and inflammation. Vitamins, dietary fatty acids, minerals, micronutrients and plant-derived flavonoids have attracted significant attention for their primary role in maintaining brain health by attenuating oxidative stress and neuroinflammation, the key culprits in neurodegenerative pathologies and age-related cognitive decline.

Purpose: Vitamin E is a fat-soluble antioxidant with isomers categorised as tocopherols and tocotrienols. Delta-tocotrienol (δ-T3) is an isomer with an unsaturated isoprenoid side chain that confers better membrane penetration and enhanced bioactivities, including scavenging of free radicals, anti-inflammatory and cholesterol-lowering effects. However, the neurodifferentiation and neurocognitive potential of δ-T3 and its bioactive conjugate δ-T3-γCD beyond its classical antioxidant properties is not known.

Methods: In the present study, using rodent-derived PC12 neuroblastoma and C6 glioblastoma cell lines, we assessed the differentiation potential of δ-T3 and its unique complex with γCyclodextrin (δ-T3-γCD). Further, an animal model of scopolamine (SC)-induced memory dysfunction was employed to evaluate the effect of δ-T3 and δ-T3-γCD on memory processes and key molecular markers.

Results: Here, we report that brain-derived cells cultured in low, nontoxic doses of δ-T3 exhibit differentiation. In the SC-induced amnesic mouse model, δ-T3 reversed object recognition memory impairment, concomitantly increasing cortical and hippocampal neural progenitor and differentiation markers, mature neuron markers and neurotrophic factors. Of note, δ-T3-γCD (δ-T3 complexed with γCyclodextrin), containing only 20.7% δ-T3, showed a stronger effect.

Conclusion: δ-T3 showed neurodifferentiation and anti-amnesic potential with improved efficacy when complexed with γCyclodextrin (δ-T3-γCD) in both cellular and mouse model systems. Cyclodextrin-enabled δ-T3 might be a useful resource for the treatment of stress- and age-related memory dysfunction.