Intranasal triptolide in mice: a strategy to reduce neuroinflammation and boost cognitive function

Area of Science:

• Pharmacology and Drug Delivery
• Neuroscience
• Biomedical Engineering

Background:

• Triptolide (TP) exhibits therapeutic potential but suffers from high systemic toxicity.
• Neurodegenerative diseases like Alzheimer's disease (AD) and neuroinflammation require effective brain-targeted therapies.
• Liposomal drug delivery systems offer a promising strategy to improve drug bioavailability and reduce side effects.

Purpose of the Study:

• To develop triptolide-loaded liposomes (TPL) for intranasal delivery.
• To evaluate the brain targeting, safety, and therapeutic efficacy of intranasal TPL in neuroinflammatory and AD models.
• To elucidate the underlying mechanisms of TPL's therapeutic effects.

Main Methods:

• Liposomes encapsulating triptolide (TPL) were prepared using thin-film hydration.
• Biodistribution of liposomes via nasal, oral, and intravenous routes was assessed using *in vivo* imaging.
• Safety and efficacy of intranasal TPL were evaluated in LPS-induced neuroinflammation and APP/PS1 AD mouse models, including behavioral, histopathological, and molecular analyses.

Main Results:

• Nasal administration resulted in superior brain accumulation of liposomes compared to other routes.
• Optimized TPL demonstrated favorable characteristics including high encapsulation efficiency and sustained release.
• Intranasal TPL exhibited reduced systemic toxicity, improved cognitive and behavioral performance, attenuated neuroinflammation, reduced amyloid-beta plaques, and modulated apoptosis and survival pathways in disease models.

Conclusions:

• Intranasal TPL is an effective strategy for enhancing brain delivery of triptolide while minimizing systemic exposure.
• The TPL system demonstrates multimodal therapeutic benefits, including anti-inflammatory, anti-amyloid, and pro-survival effects.
• Nasal TPL holds significant therapeutic promise for treating neurodegenerative disorders like Alzheimer's disease.