Novel neuroprotective effects with O-benzyl derivative of pralidoxime in soman-intoxicated rodents

• Published in: European journal of pharmacology 2005-10, Vol.521 (1), p.59-69
• Main Authors: Loke, Weng-Keong, Sim, Meng-Kwoon, Go, Mei-Lin
• Format: Article
• Language: English
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; Acetylcholine; Acetylcholine - metabolism; Analysis of Variance; Animals; Anticonvulsant effect; Anticonvulsants - pharmacology; Atropine - pharmacology; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacology; Biological and medical sciences; Cholinesterase Inhibitors - toxicity; Cholinesterase Reactivators - pharmacology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine - metabolism; Drug Synergism; Electroencephalography - drug effects; Female; Homovanillic Acid - metabolism; Hydroxyindoleacetic Acid - metabolism; Medical sciences; Mice; Microdialysis; Neuroprotective Agents - pharmacology; Non-reactivation effect; Oximes; Pharmacology. Drug treatments; Pralidoxime Compounds - chemistry; Pralidoxime Compounds - pharmacology; Pralidoxime derivative; Pyridinium Compounds - chemistry; Pyridinium Compounds - pharmacology; Rats; Rats, Wistar; Sedative effect; Seizures - mortality; Seizures - physiopathology; Seizures - prevention & control; Serotonin - metabolism; Soman - toxicity; Soman poisoning; Survival Rate; Time Factors
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2005.07.033

Pharmacological properties of oxime reactivators, not related to its ability to regenerate or reactivate nerve agent-inhibited acetylcholinesterase located at nerve synapses, have been reported to be important in protecting against poisoning by the nerve agent soman. Such non-reactivation effects have thus far been associated only with bispyridinium oximes. This study investigated the possibility of creating similar non-reactivation therapeutic effects in the mono-pyridinium ring oxime, pralidoxime (2-PAM) through attachment of alkyl groups of increasing chain length to the oxime functional group. Of the 4 derivatives investigated, only the O-benzyl derivative displayed strong sedative effects in mice and mitigated the development of motor convulsions following soman challenge (1.8 × LD 50, subcutaneous). Anticonvulsant effects of this compound were enhanced by co-administration of a non-anticonvulsant dose of atropine sulfate. Administration of equivalent amount of other O-derivatives of pralidoxime failed to elicit similar anticonvulsant actions. Electroencephalographic (EEG) and histopathological studies using the rat model, intoxicated with a lethal dose (1.6 × LD 50, s.c.) of soman, confirmed O-benzyl derivative neuroprotective capabilities when used as a pretreatment drug. Microdialysis studies revealed that its neuroprotective effect is related to its ability to attenuate soman-induced increase in acetylcholine.