Nitrone spin trapping compound N-tert-butyl-alpha-phenylnitrone prevents seizures induced by anticholinesterases.
The neuroprotection afforded by spin trapping agents such as N-tert-butyl-alpha-phenylnitrone (PBN) has lent support to the hypothesis that increased production of reactive oxygen species (ROS) is a major contributing factor to excitotoxicity, aging and cognitive decline. Little is known, however, about the pharmacological properties of PBN. We have compared the acute effects of PBN on the development of seizures induced by the irreversible acetylcholinesterase (AChE) inhibitor diisopropylphosphorofluoridate (DFP), the reversible AChE inhibitor physostigmine (PHY), the muscarinic cholinergic receptor agonist pilocarpine (PIL) and the glutamatergic receptor agonist kainic acid (KA). Rats were sacrificed 90 min after the injection of seizure-inducing agents. In situ hybridization was used to detect the induction of immediate early gene (IEG) c-fos and c-jun mRNA's and the levels of AChE mRNA. The activity of AChE was visualized by AChE staining and quantified using an in vitro AChE assay. The seizures correlated with the induction of IEG mRNA's with all agents used. The pre-treatment with 150 mg/kg of PBN prevented DFP- and PHY-induced seizures and the related expression of IEG mRNA's, but had no effect on PIL- or KA-induced seizures and associated IEG mRNA's changes. PBN prevented seizures and significantly protected AChE activity against DFP inhibition when given before, but not when given after DFP. This study shows that PBN specifically protects against anticholinesterase-induced seizures by reversible protection of AChE activity and not by the blockade of muscarinic or glutamate receptors, reactivation of AChE or scavenging of ROS. The anticholinesterase properties should be considered when using PBN in studies of cholinergic dysfunction.
Zivin
M
M
Institute of Pathophysiology, University of Ljubljana, Medical School, Slovenia.
Milatovic
D
D
Dettbarn
W D
WD
D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002800:Cholinesterase Inhibitors; D003497:Cyclic N-Oxides; D018690:Excitatory Amino Acid Agonists; D016762:Genes, fos / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D017403:In Situ Hybridization; D007531:Isoflurophate; D007608:Kainic Acid; D008297:Male; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D010830:Physostigmine; D010862:Pilocarpine; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D013113:Spin Labels; D019097:Spin Trapping
D000927:Anticonvulsants; D002800:Cholinesterase Inhibitors; D003497:Cyclic N-Oxides; D018690:Excitatory Amino Acid Agonists; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D012333:RNA, Messenger; D013113:Spin Labels; D010862:Pilocarpine; D007531:Isoflurophate; C029217:phenyl-N-tert-butylnitrone; D010830:Physostigmine; D000110:Acetylcholinesterase; D007608:Kainic Acid