Efficacy of huperzine in preventing soman-induced seizures, neuropathological changes and lethality.
Huperzine A (HUP) is a potent reversible inhibitor of acetylcholinesterase (AChE) that crosses the blood-brain barrier. Its ability to prevent seizures and subsequent hippocampal neuropathological changes induced by the organophosphate soman was studied in guinea pigs. Results were compared to guinea pigs treated with pyridostigmine (PYR, 0.2 mg/kg, subcutaneously). HUP pretreatment at 0.5 mg/kg, intraperitoneally, totally prevented seizures and ensured the survival of all animals for 24 h after intoxication. Hippocampal tissue was then free of any neuronal damage. Comparatively, all animals pretreated with PYR exhibited epileptic activity after soman poisoning and five of six animals died. Examination of the hippocampus of the only surviving guinea pig pretreated with PYR showed extensive neuropathological changes. Although HUP or PYR induced similar inhibitions of blood AChE activity, only HUP pretreatment led to a decrease in central AChE activity. In binding studies on guinea-pig brain homogenates, HUP had no affinity for muscarinic, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and gamma-aminobutyric acid (GABA)A receptors and only a very low one for N-methyl-D-aspartate (NMDA) receptors. In conclusion, HUP, unlike PYR, protects against soman-induced convulsions and neuropathological changes in the hippocampus. This efficacy seems to be related to a protection by HUP of both peripheral and central stores of AChE.
Lallement
G
G
Unité de Neurotoxicologie, CRSSA, La Tronche, France.
Veyret
J
J
Masqueliez
C
C
Aubriot
S
S
Burckhart
M F
MF
Baubichon
D
D
D000470:Alkaloids; D000818:Animals; D001921:Brain / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D004569:Electroencephalography; D006168:Guinea Pigs; D006624:Hippocampus / Q000473:pathology*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011729:Pyridostigmine Bromide / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D012717:Sesquiterpenes / Q000378:metabolism / Q000627:therapeutic use*; D012999:Soman
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D012717:Sesquiterpenes; C050426:huperzine A; D012999:Soman; D011729:Pyridostigmine Bromide