Crafting cationic lecithmer nanocomposites as promising wagons for brain targeting of cinnamaldehyde: Accentuated neuroprotection via downregulation of Aβ1-42/p-tau crosstalk

Alzheimer's disease (AD) is a prevalent neurodegenerative ailment responsible for 80% of senile dementia cases globally. Its pathophysiology relies on the functional interaction between amyloid beta peptide (Aβ) and tau protein which provokes damage to neurons and cognitive impairment. Cinnamaldehyde (CMD), the chief component of cinnamon bark, elicits inhibitory effects on the aggregation of misfolded Aβ and tau proteins which marks it a promising candidate for managing AD. Nevertheless, CMD hydrophobic trait triggers curiosity for competent drug delivery systems which could snowball its bioavailability without influencing its bioactivity. Herein, the assembly of a novel hybrid nanoparadigm, cationic lecithmer nanocomposites (CLNCs), was examined for its possible exploitation in brain targeting of CMD for AD management. CLNCs were tailored via a modified solvent emulsification–evaporation technique according to Box-Behnken design for election of the optimum formulation employing Design-Expert® software. Additionally, the efficacy of the optimal nano-cargo versus crude CMD was investigated using AlCl3 model of AD in rats. The optimized formulation disclosed nanoscaled spherical composites (137.72 nm), reasonable entrapment efficiency (70.14%), controlled accumulative release over 24 h (63.28%) and consolidated kinetic stability. Results of behavioral tests (Y-maze, novel object recognition) revealed an improvement in cognitive functions especially with CMD-CLNCs compared to rats with AlCl3-induced dementia. Besides, mRNA expression of NF-κB, APP, BACE1, and the protein expression of Aβ1-42 and p-tau/tau in cerebral tissues were more efficiently downregulated with CMD-CLNCs compared to crude CMD. Overall, our results could verify the hypothesized superiority of CMD-CLNCs in AD tackling through interference with Aβ/tau interplay.