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

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.

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.

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.

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.

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.