Galantamine prevents soman-induced apoptotic cell death in the guinea pig brain

Galantamine, a drug approved for treatment of Alzheimer's disease, prevents the acute toxicity and the neurodegeneration induced by organophosphorous poisons, including soman. The present study was designed to identify soman-induced neurotoxicity and its protection by galantamine. Male pre-pubertal guinea pigs were treated with: (i) saline (0.5 ml/kg, im), (ii) galantamine (8 mg/kg, im), (iii) 1xLD50 soman (28 microg/kg, sc), or (iv) galantamine 30 min before soman. All animals, except those challenged with soman alone, survived. Only 50% of the soman-challenged, untreated guinea pigs survived; about 75% of the survivors had mild or severe signs of intoxication and were studied herein. At 24 h after each treatment, animals were euthanized, and their brains removed for analysis of cell viability, enzyme activity, protein expression and neuronal death.;In histological studies, large numbers of neurons were stained with Fluoro Jade-B (FJ-B), a fluorescent marker of neurodegeneration, in the amygdala, piriform cortex, and cerebral cortex, but rarely in the hippocampus of soman-injected animals. TUNEL-positive cells were also visualized in different brain regions of soman-challenged guinea pigs. Caspase 3/7 activity was higher in the brains taken from animals 2h after their challenge with soman than in the brains of control animals. In the brains of soman-injected guinea pigs that were pre-treated with galantamine, there were no FJ-B-positive cells and no TUNEL-positive cells. In addition, caspase activity in the brain of soman-challenged guinea pigs that were treated with galantamine was comparable to control.;These results indicate that: (i) neurodegeneration induced by soman is in part a result of the activation of a caspase-dependent apoptotic pathway, and (ii) pre-treatment with galantamine can effectively prevent soman-induced neurodegeneration.