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Intranasal rifampicin for Alzheimer's disease prevention
Tomohiro Umeda1, Akiko Tanaka2, Ayumi Sakai1
1Department of Translational Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan.
Introduction:
Oral rifampicin has been shown to significantly reduce amyloid β (Aβ) and tau pathologies in mice. However, it shows occasional adverse effects such as liver injury in humans, making its use difficult for a long period.
Methods:
To explore safer rifampicin treatment, APPOSK mice, a model of Alzheimer's disease, were treated with rifampicin for 1 month via oral, intranasal, and subcutaneous administration, and its therapeutic efficacy and safety were compared.
Results:
Intranasal or subcutaneous administration of rifampicin improved memory more effectively than oral administration. The improvement of memory was accompanied with the reduction of neuropathologies, including Aβ oligomer accumulation, tau abnormal phosphorylation, and synapse loss. Serum levels of a liver enzyme significantly rose only by oral administration. Pharmacokinetic study revealed that the level of rifampicin in the brain was highest with intranasal administration.
Discussion:
Considering its easiness and noninvasiveness, intranasal administration would be the best way for long-term dosing of rifampicin.
Insights
Intranasal rifampicin effectively treats Alzheimer's disease (AD) by reducing brain amyloid and tau pathologies. This method is safer and more effective than oral administration for long-term AD treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Alzheimer's Disease Research
Background:
- Oral rifampicin reduces amyloid-beta (Aβ) and tau pathologies in mouse models of Alzheimer's disease (AD).
- Oral rifampicin can cause adverse effects like liver injury in humans, limiting its long-term use for AD treatment.
Purpose of the Study:
- To investigate safer and more effective administration routes for rifampicin in treating AD.
- To compare the therapeutic efficacy and safety of oral, intranasal, and subcutaneous rifampicin in an AD mouse model.
Main Methods:
- APPOSK mice, a model for Alzheimer's disease, were administered rifampicin via oral, intranasal, and subcutaneous routes for one month.
- Therapeutic efficacy was assessed by memory improvement and reduction of neuropathologies (Aβ oligomers, tau phosphorylation, synapse loss).
- Safety was evaluated by monitoring serum liver enzyme levels, and drug distribution was studied via pharmacokinetics.
Main Results:
- Intranasal and subcutaneous rifampicin administration showed superior memory improvement compared to oral administration.
- Neuropathological hallmarks of AD, including Aβ oligomers, abnormal tau phosphorylation, and synapse loss, were reduced by intranasal and subcutaneous rifampicin.
- Elevated liver enzymes were observed only with oral rifampicin administration, indicating better safety for other routes.
- Brain concentrations of rifampicin were highest following intranasal administration.
Conclusions:
- Intranasal administration of rifampicin offers a safer and more effective therapeutic strategy for Alzheimer's disease compared to oral delivery.
- Intranasal delivery is recommended for long-term rifampicin dosing due to its non-invasiveness, ease of administration, and enhanced brain penetration.