Drug Development

Area of Science:

• Nanotechnology
• Neuroscience
• Pharmacology

Background:

• Glycogen Synthase Kinase 3β (GSK-3β) deregulation is implicated in mood disorders and neurodegenerative diseases like Alzheimer's disease (AD).
• Lithium (Li+) inhibits GSK-3β but faces systemic toxicity challenges, limiting its therapeutic use, especially at effective brain concentrations.
• Novel delivery systems are needed to target the brain with Li+ while avoiding systemic side effects.

Purpose of the Study:

• To develop and evaluate a novel brain-specific drug delivery system for lithium.
• To assess the efficacy of this system in modulating GSK-3β activity and addressing AD neuropathology.

Main Methods:

• Development of gold nanoparticles (AuNPs) functionalized with glutathione and loaded with Li+ (a-LiG-AuNPs), forming 250 nm aggregates.
• Evaluation of intracellular Li+ release and GSK-3β inhibition in cultured SH-SY5Y cells.
• Intranasal administration of a-LiG-AuNPs in mice to assess brain delivery, GSK-3β phosphorylation, and neuropathological effects.

Main Results:

• a-LiG-AuNPs significantly increased GSK-3β phosphorylation (pGSK-3β-S9) in cells, even at low Li+ concentrations ineffective with traditional salts.
• Intranasal administration in mice led to direct brain accumulation of a-LiG-AuNPs, increasing pGSK-3β-S9 in situ without affecting plasma Li+ levels or causing gliosis.
• a-LiG-AuNP treatment protected hippocampal neurons from tau-induced synaptotoxicity and improved memory in a mouse model of AD.

Conclusions:

• a-LiG-AuNPs provide an effective method for targeted brain delivery of Li+.
• This approach holds potential for treating GSK-3β-dependent neurological diseases like AD.
• The system offers a promising strategy to avoid systemic Li+ toxicity.