Novel neuroprotective effects with O-benzyl derivative of pralidoxime in soman-intoxicated rodents.
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 x LD50, 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 x LD50, 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.
Loke
Weng-Keong
WK
Centre for Chemical Defence, DSO National Laboratories, 11 Stockport Road, Singapore 118230, Republic of Singapore. lwengkeo@dso.org.sg
Sim
Meng-Kwoon
MK
Go
Mei-Lin
ML
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000109:Acetylcholine / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D051379:Mice; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010091:Oximes; D011220:Pralidoxime Compounds / Q000737:chemistry / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control; D012701:Serotonin / Q000378:metabolism; D012999:Soman / Q000633:toxicity*; D015996:Survival Rate; D013997:Time Factors
D000927:Anticonvulsants; D001555:Benzene Derivatives; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D018696:Neuroprotective Agents; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D001285:Atropine; D012999:Soman; C022870:asoxime chloride; D000109:Acetylcholine; C028797:pralidoxime; D004298:Dopamine; D006719:Homovanillic Acid