Mishra_2026_J.Pharmacol.Exp.Ther_393_104788

Alzheimer's disease is a progressive neurodegenerative disorder defined by the presence of extracellular amyloid-beta (Abeta) plaques and intracellular neurofibrillary tangles, which together drive cognitive decline and memory impairment. Current therapies provide only symptomatic relief, highlighting the urgent need for disease-modifying strategies targeting the underlying pathology. Piperine, a plant-derived alkaloid with neuroprotective, antioxidant, and antiamyloidogenic properties, has shown preclinical efficacy against Abeta toxicity. However, its clinical translation is limited by poor aqueous solubility and low bioavailability. The present study aimed to develop and characterize spray-dried piperine-loaded solid dispersion (PIP@SDs) to overcome these pharmacokinetic barriers and enhance neuroprotective efficacy. PIP@SDs were prepared using spray drying with leucine as a carrier to improve solubility and stability. Solid-state characterization was performed using differential scanning calorimetry, Fourier-transform infrared spectroscopy, and powdered X-ray diffraction to confirm amorphization and molecular interactions. PIP@SDs demonstrated enhanced solubility, achieving 97.5% drug release in 24 hours, compared with pure drug and improved flow properties suitable for pharmaceutical manufacturing. In SH-SY5Y cells, PIP@SDs markedly increased viability after Abeta insult (from 50.2% to 80.8%, P < .0001), reduced oxidative stress, stabilized mitochondrial membrane potential, restored calcium equilibrium, and lowered apoptosis levels relative to free piperine. Notably, PIP@SDs inhibited cholinesterase activity and prevented Abeta aggregation, with all effects confirmed through quantitative and imaging analyses. In closing, by substantially enhancing solubility and bioavailability and providing superior neuroprotection against Abeta-mediated toxicity, spray-dried PIP@SDs offer a novel, multifunctional platform that supports their continued research as a promising candidate for disease-modifying interventions in Alzheimer's and related neurodegenerative disorders. SIGNIFICANCE STATEMENT: Poor aqueous solubility and limited bioavailability restrict the therapeutic potential of many neuroprotective natural compounds. This study demonstrates that spray-dried piperine-leucine solid dispersions markedly enhance piperine dissolution and significantly attenuate amyloid-beta-induced oxidative stress, mitochondrial dysfunction, and apoptosis in neuronal cells. These findings highlight a pharmacologically relevant formulation strategy that improves the bioactivity of piperine and supports its development as a multifunctional therapeutic candidate targeting oxidative and mitochondrial pathways implicated in Alzheimer disease.