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• W4385851346 abstract "The brain-derived neurotrophic factor (BDNF)/TrkB pathway plays a crucial role in neural plasticity and neuronal survival but is often deficient in neurodegenerative diseases like Alzheimer’s disease (AD). CF3CN acts as a specific TrkB agonist that displays therapeutic effects in the AD mouse model, but its brain/plasma ratio (B/P ratio) distribution is not satisfactory. To increase its brain exposure, we synthesized several derivatives and employed nanoparticle (NP) formulation to optimize the most potent #2 derivative’s in vivo PK profiles. We generated stable #2-loaded zein/lactoferrin composite NPs (#2/zein/LF) using the antisolvent co-precipitation method. In vivo PK studies revealed that nanoencapsulation improved #2’s oral bioavailability by approximately 2-fold and significantly enhanced its plasma Cmax and t1/2, but the brain profiles were comparable. Pharmacodynamics showed that #2/zein/LF activates TrkB signaling that phosphorylates asparagine endopeptidase (AEP) T322 and decreases its enzymatic activity, resulting in reduced AEP-cleaved amyloid precursor protein and Tau fragments in the brains of AD mice, correlating with its PK profiles. After 3 months of treatment in 3xTg mice, #2/zein/LF decreased AD pathologies and alleviated cognitive dysfunction. Hence, zein/LF composite nanoencapsulation is a promising drug delivery method for improving the PK profiles of a potential preclinical candidate for treating neurodegenerative diseases." @default.
• W4385851346 created "2023-08-17" @default.
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• W4385851346 date "2023-08-16" @default.
• W4385851346 modified "2023-10-14" @default.
• W4385851346 title "Zein-Based Nanoparticles Improve the Therapeutic Efficacy of a TrkB Agonist toward Alzheimer’s Disease" @default.
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• W4385851346 doi "https://doi.org/10.1021/acschemneuro.3c00401" @default.
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• W4385851346 hasPublicationYear "2023" @default.
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