Intranasal administration of dantrolene increased brain concentration and duration

Area of Science:

• Neuroscience
• Pharmacology
• Drug Delivery

Background:

• Dantrolene shows neuroprotective potential in neurodegenerative diseases.
• Limited central nervous system (CNS) penetration hinders dantrolene's efficacy.
• Novel drug delivery methods are needed to enhance brain targeting.

Purpose of the Study:

• To compare intranasal versus oral dantrolene administration for brain penetration.
• To evaluate the impact of blood-brain barrier (BBB) efflux pump inhibitors on dantrolene brain concentration.
• To assess the safety of chronic intranasal dantrolene in mice.

Main Methods:

• C57BL/6 mice received single doses of intranasal or oral dantrolene (5mg/kg).
• Dantrolene brain and plasma concentrations were measured over 180 minutes.
• Co-administration with P-gp/BCRP inhibitors (nimodipine, elacridar) was used to study clearance.
• Long-term safety was assessed via olfaction and motor coordination tests.

Main Results:

• Intranasal dantrolene sustained brain concentrations for 180 minutes; oral administration showed negligible levels by 120 minutes.
• BBB pump inhibitors did not significantly increase peak brain dantrolene concentrations.
• Chronic intranasal dantrolene administration did not impair olfaction or motor function.

Conclusions:

• Intranasal administration is a superior route for increasing dantrolene concentration and duration in the brain.
• This delivery method bypasses limitations associated with oral administration and BBB efflux.
• Intranasal dantrolene presents a promising strategy for neurodegenerative disease treatment with a favorable safety profile.