Galantamine counteracts development of learning impairment in guinea pigs exposed to the organophosphorus poison soman: Clinical significance

Abstract

Galantamine, a drug used to treat Alzheimer’s disease, protects guinea pigs against the acute toxicity and lethality of organophosphorus (OP) compounds, including soman. Here, we tested the hypothesis that a single exposure of guinea pigs to 1xLD50 soman triggers cognitive impairments that can be counteracted by galantamine. Thus, animals were injected intramuscularly with saline (0.5 ml/kg) or galantamine (8 mg/kg) and 30 min later injected subcutaneously with soman (26.3 µg/kg) or saline. Cognitive performance was analyzed in the Morris water maze (MWM) four days or three months after the soman challenge. Fifty percent of the saline-injected animals that were challenged with soman survived with mild-to-moderate signs of acute toxicity that subsided within a few hours. These animals showed no learning impairment and no memory retention deficit, when training in the MWM started four days post-soman challenge. In contrast, animals presented significant learning impairment when testing started three months post-challenge. Though the magnitude of the impairment correlated with the severity of the acute toxicity, animals that presented no or only mild signs of toxicity were also learning impaired. All guinea pigs that were treated with galantamine survived the soman challenge with no signs of acute toxicity and learned the MWM task as control animals, regardless of when testing began. Galantamine also prevented memory extinction in both saline-and soman-challenged animals. In conclusion, learning impairment develops months after a single exposure to 1xLD50 soman, and galantamine prevents both the acute toxicity and the delayed cognitive deficits triggered by this OP poison.

Animal Models That Best Reproduce the Clinical Manifestations of Human Intoxication with Organophosphorus Compounds

“…Guinea pigs, too, develop cognitive deficits long after their exposure to soman (Mamczarz et al, 2011;Pereira et al, 2012). Three months after surviving the challenge with 1.0Â LD 50 soman, prepubertal female guinea pigs present spatial learning impairment in the Morris water maze (Mamczarz et al, 2011) and adult male guinea pigs present both spatial learning and memory retention deficits (Pereira et al, 2012). …”

Assessment of Potential Long Term Health Effects on Army Human Test Subjects of Relevant Biological and Chemical Agents, Drugs, Medications and Substances

“…A case of renal failure as a result of tetracycline use 45 has been reported, but the patient had pre-existing polycystic kidney disease as an underlying condition. 195 A recent retrospective cohort study, however, found a possible association between the tetracycline-class antibiotic use and the onset of inflammatory bowel disease (IBD), ulcerative colitis and Crohn's Disease. 196 In this study, Margolis and co-workers looked at the association in over 94,000 individuals using The Health Improvement Network database of the United Kingdom.…”

“…196 In this study, Margolis and co-workers looked at the association in over 94,000 individuals using The Health Improvement Network database of the United Kingdom. They calculated the hazard ratio (HR) for developing IBD subsequent to any exposure to a tetracycline antibiotic to have been 1 195 It is unclear why the use of tetracycline antibiotics would cause inflammatory bowel disease or Crohn's Disease in some individuals, but alterations in gut flora, gut cellular activity, or T-cell activity due to antibiotic use might be involved. 197,198 …”

Galantamine prevents long-lasting suppression of excitatory synaptic transmission in CA1 pyramidal neurons of soman-challenged guinea pigs

“…Persistent neurological dysfunctions and structural brain damage that resemble those presented by humans exposed to nerve agents have been successfully reproduced in different animal models, including rats, mice, guinea pigs, and non-human primates. It is also noteworthy that these neurological deficits have been detected in animals that at the time of the OP exposure were either asymptomatic or presented only mild signs of acute toxicity (Kassa et al, 2002; Filliat et al, 2007; Mamczarz et al, 2011). …”

“…In recent years, galantamine emerged as an effective medical countermeasure to prevent both the acute and delayed toxicity of OP compounds (Albuquerque et al, 2006; Aracava et al, 2009; Gullapalli et al, 2010; Hilmas et al, 2009; Mamczarz et al, 2011; Pereira et al, 2010). Thus, the present study was designed to test the hypothesis that an acute in vivo exposure to soman suppresses glutamatergic synaptic transmission in CA1 pyramidal neurons and that this effect can be prevented by pretreatment with galantamine.…”