Oxime Therapy for Brain AChE Reactivation and Neuroprotection after Organophosphate Poisoning

Area of Science:

• Neuroscience
• Pharmacology
• Biotechnology

Background:

• Organophosphorus (OP) poisoning treatment is limited by antidotes' inability to cross the blood-brain barrier (BBB).
• Acetylcholinesterase (AChE) inhibitors are common in OP poisoning, leading to neurological damage.
• Effective delivery of AChE reactivators to the brain is crucial for treating OP-induced neurotoxicity.

Purpose of the Study:

• To develop modified cationic liposomes capable of crossing the BBB.
• To evaluate the efficacy of these liposomes in delivering pralidoxime chloride (2-PAM) to the brain.
• To assess the neuroprotective effects of liposomal 2-PAM against organophosphorus poisoning.

Main Methods:

• Liposomes were formulated using phosphatidylcholine and imidazolium surfactants, with varying surfactant/lipid ratios.
• Physicochemical properties, drug release profiles, hemolytic activity, and hemagglutination were assessed.
• BBB penetration, 2-PAM pharmacokinetics, in vivo AChE reactivation, and neuronal death in the hippocampus were evaluated in animal models.

Main Results:

• Modified liposomes demonstrated successful BBB penetration and brain delivery of 2-PAM.
• In vivo studies showed significant reactivation of brain AChE (25%) in rats poisoned with paraoxon (POX).
• Intravenous administration of liposomal 2-PAM significantly reduced POX-induced neuronal death in the hippocampus of mice.

Conclusions:

• Imidazolium-based cationic liposomes are effective carriers for delivering AChE reactivators across the BBB.
• This liposomal formulation offers a promising strategy for enhancing the treatment of organophosphorus poisoning.
• The findings highlight the potential of liposomal 2-PAM in mitigating OP-induced neurotoxicity and neuronal loss.