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

      Kulkarni, Girish S.; Albuquerque, E. X.; Pereira, Edna F. R. (2012)
      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 μg/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.