Oxime Therapy for Brain AChE Reactivation and Neuroprotection after Organophosphate Poisoning

Abstract

One of the main problems in the treatment of poisoning with organophosphorus (OPs) inhibitors of acetylcholinesterase (AChE) is low ability of existing reactivators of AChE that are used as antidotes to cross the blood-brain barrier (BBB). In this work, modified cationic liposomes were developed that can penetrate through the BBB and deliver the reactivator of AChE pralidoxime chloride (2-PAM) into the brain. Liposomes were obtained on the basis of phosphatidylcholine and imidazolium surfactants. To obtain the composition optimized in terms of charge, stability, and toxicity, the molar ratio of surfactant/lipid was varied. For the systems, physicochemical parameters, release profiles of the substrates (rhodamine B, 2-PAM), hemolytic activity and ability to cause hemagglutination were evaluated. Screening of liposome penetration through the BBB, analysis of 2-PAM pharmacokinetics, and in vivo AChE reactivation showed that modified liposomes readily pass into the brain and reactivate brain AChE in rats poisoned with paraoxon (POX) by 25%. For the first time, an assessment was made of the ability of imidazolium liposomes loaded with 2-PAM to reduce the death of neurons in the brains of mice. It was shown that intravenous administration of liposomal 2-PAM can significantly reduce POX-induced neuronal death in the hippocampus.

Therapy of Organophosphate Poisoning via Intranasal Administration of 2-PAM-Loaded Chitosomes

“…Such a disadvantage is associated with the hydrophilicity of the oxime and its permanent positive charge [10]. There are several main directions for improving oxime therapy: an active search for new, more effective reactivators [13][14][15][16] and the development of oxime formulations (including nanocarriers) that ensure their passage through biological barriers, i.e., BBB [17,18]. The second strategy has been widely studied and described in a previous review [19].…”

“…Positively charged compounds can increase retention of the liposomes in the nasal cavity due to electrostatic interactions between nanoparticles and mucosal components [21]. In the case of liposomes, a positive charge can be achieved by the introduction of cationic surfactants [17,[27][28][29], lipids, or polymers [30]. There are many publications devoted to covering liposomes with different types of chitosan (Cs), which can be used to modify their functionality and are aptly described in recent reviews [31,32].…”

Transdermal Delivery of 2-PAM as a Tool to Increase the Effectiveness of Traditional Treatment of Organophosphate Poisoning

“…Table 1 shows that there is a slight increase in the hydrodynamic diameter of the transfersomes during storage (no more than 6%). According to the literature data, liposomal systems are characterized by a slight increase in size and polydispersity index during storage [ 37 , 38 , 39 , 40 ]. It is worth noting that changes in size in most cases were insignificant; however, it is mentioned that fresh liposomes show greater efficiency than liposomes stored for a long time [ 41 ].…”

Complexation of Oligo- and Polynucleotides with Methoxyphenyl-Functionalized Imidazolium Surfactants

“…The determination of hydrodynamic diameter (D H = 2R H , nm) and zeta potential of ONu and DNA molecules, as well as their complexes with surfactants, was carried out on a ZetaSizer Nano particle analyzer (Malvern Instruments Ltd., Worcestershire, UK) [49][50][51]. The hydrodynamic radius of the particles (R H ) was calculated based on the Stokes-Einstein Equation (1) [52][53][54]:…”

“…After mixing the components, incubation was carried out for 1 h at 37 • C. Hemagglutination was observed with the naked eye [61] and assessed using a Nikon Eclipse Ci-S fluorescent microscope (Nikon, Nanjing, China). A suspension of erythrocytes in 0.9% NaCl and a mixture of type A (II) and B (III) erythrocytes were used as negative and positive control of agglutination, respectively [51].…”