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Xanthohumol (XH) shows good neuroprotection against Alzheimer's Disease (AD). However, it exhibits poor solubility and low oral bioavailability. The current research presents the formulation, optimization, and characterization of XH-loaded nanostructured lipid carriers (XH-NLCs) to enhance oral bioavailability and therapeutic efficacy of XH in an aluminium chloride-induced rat model of Alzheimer's disease (AD). XH-NLCs were formulated utilizing hot high-pressure homogenization and probe sonication techniques. The processing parameters, including total lipid-to-drug ratio, solid lipid-to-liquid lipid ratio, and surfactant concentration were optimized using the Box-Behnken design. Optimized liquid XH-NLCs showed a mean particle size of 81.48 ± 4.02 nm, zeta potential of -16.3 ± 4.58 mV, and entrapment efficiency of 68 ± 2.46%, whereas, the reconstituted S-XH-NLCs (post-lyophilization) showed 113.8 nm particle size, -20.3 mV zeta potential, and 65% entrapment efficiency. Scanning electron microscopy and differential scanning calorimetry revealed that XH was molecularly dispersed in the amorphous state within the NLCs matrix. XH-NLCs showed enhanced in-vitrodrug release by 4.93-fold as compared to its naïve form. Pharmacokinetic analysis revealed a 24.7-fold increase in Cmax and a 6.25-fold increase in AUC0-t(2497.37 ng/mL·h) for XH in NLCs, with 11.3-fold higher brain availability. Pharmacodynamic evaluations indicated significant improvements in cognitive and motor functions, as well as reductions in AChE, Aβ, oxidative stress, and neuroinflammation, demonstrating the potential of XH-NLCs in AD therapy. These results highlight the potential of XH-NLCs for further development as a therapeutic strategy for AD

Xanthohumol (XH) is a prenylated flavonoid that possesses neuroprotective effects by increasing the levels of dopamine (DA), reducing oxidative stress, and neuroinflammation against Parkinson's disease (PD). However, the neuroprotective efficacy of XH in managing PD is limited by its low solubility, poor bioavailability, and less blood-brain barrier (BBB) permeability leading to decreased therapeutic activity. To overcome these limitations, XH-loaded solid dispersion (SD) has been formulated using the Central Composite Design (CCD) approach. The optimized formulation was evaluated by determining the angle of repose, drug loading, percentage drug release, PXRD, DSC, FTIR, and SEM. The results of PXRD, DSC, and SEM demonstrated the formation of SD. The XH-SD showed a 6.45-fold enhancement in dissolution rate, a 12.7-fold increase in Cmax,and 26.11-fold increase in XH's area under curve (AUC) as compared to the naïve XH. In the pharmacokinetic studies, XH-SD showed a 42.20 folds increase in relative bioavailability(0-∞)compared to naïve XH. To assess pharmacodynamic effects, PD was induced using rotenone. The motor and non-motor functions were evaluated by assessing various behavioral parameters such as catalepsy, spontaneous locomotor activity and muscle coordination test. The formulation exhibited dose-dependent effects, with both low and high doses of XH-SD resulting in significant enhancements (P < 0.001) in motor functions in rats induced with PD. Furthermore, biochemical estimations showed that XH-SD at both doses increased the levels of dopamine (DA), and reduced oxidative stress and neuroinflammation.