Pretreatment of Guinea Pigs with Galantamine Prevents Immediate and Delayed Effects of Soman on Inhibitory Synaptic Transmission in the Hippocampus

Abstract

Galantamine has emerged as a potential antidote to prevent the acute toxicity of organophosphorus (OP) compounds. Changes in inhibitory GABAergic activity in different brain regions can contribute to both induction and maintenance of seizures in subjects exposed to the OP nerve agent soman. Here, we tested the hypothesis that galantamine can prevent immediate and delayed effects of soman on hippocampal inhibitory synaptic transmission. Spontaneous inhibitory postsynaptic currents (IPSCs) were recorded from CA1 pyramidal neurons in hippocampal slices obtained at 1 h, 24 h, or 6 to 9 days after the injection of guinea pigs with saline (0.5 ml/kg i.m.), 1ϫLD 50 soman (26.3 g/kg s.c.), galantamine (8 mg/kg i.m.), or galantamine at 30 min before soman. Soman-challenged animals that were not pretreated showed mild, moderate, or severe signs of acute intoxication. At 1 h after the soman injection, the mean IPSC amplitude recorded from slices of mildly intoxicated animals and the mean IPSC frequency recorded from slices of severely intoxicated animals were larger and lower, respectively, than those recorded from slices of control animals. Regardless of the severity of the acute toxicity, at 24 h after the soman challenge the mean IPSC frequency was lower than that recorded from slices of control animals. At 6 to 9 days after the challenge, the IPSC frequency had returned to control levels, whereas the mean IPSC amplitude became larger than control. Pretreatment with galantamine prevented somaninduced changes in IPSCs. Counteracting the effects of soman on inhibitory transmission can be an important determinant of the antidotal effectiveness of galantamine.

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

“…As in other studies (Alexandrova et al, 2010; Aracava et al, 2009; Gullapalli et al, 2010), daily weight gain and gross behavior of galantamine-treated animals were comparable to those of control animals (data not shown).…”

“…In animals that reached stages 0–3, signs of acute intoxication were not life-threatening and subsided within a few hours after the soman challenge. In the present study, animals were euthanized according to the IACUC-approved protocol as soon as they reached stages 4–5 because, in more than 80% of these animals, signs of acute toxicity quickly become life-threatening (Alexandrova et al, 2010). Twenty six out of the 50 soman-injected guinea pigs presented signs of acute toxicity that did not advance beyond stage 3 and were tested behaviorally at four days or three months after the injection of the nerve agent.…”

“…We have demonstrated that galantamine, a drug approved for treatment of Alzheimer’s disease (Corey-Bloom, 2003), effectively counteracts the lethality and the acute toxicity of OPs in guinea pigs (Albuquerque et al, 2006). Functional analyses of synaptic transmission and plasticity, histological evaluation of neuronal viability, and magnetic resonance imaging (MRI) analysis of the structural integrity of the brains of nerve agent-challenged guinea pigs subjected to different treatments provided additional evidence that galantamine is an effective and safe antidote against the acute toxicity induced by OPs (Alexandrova et al, 2010; Alkondon et al 2009; Gullapalli et al, 2010). …”

Muscarinic excitation of parvalbumin‐positive interneurons contributes to the severity of pilocarpine‐induced seizures

“…In addition, a pathological rise in ACh would also be expected to inhibit GABA release from PV terminals via the activation of M 2 mAChRs, 53,54 which could further impair PV circuit function during organophosphate-induced seizures. 55 Therefore, anticonvulsive mechanisms that prevent both cholinergic overexcitation and presynaptic inhibition of PV cells could be useful therapeutic avenues to explore in the future.…”

[+]-Huperzine A Protects Against Soman Toxicity in Guinea Pigs

“…The side effects of physostigmine treatment can be antagonized by treatment with scopolamine [7]. Although the reversible AChE inhibitors donepezil and galantamine are being evaluated as pretreatments against organophosphates and CWNA exposure, development of more effective pretreatment drugs that can readily pass through the BBB and lack CNS side effects are essential [8,9]. Additionally, a therapeutic agent that has multiple neuroprotective properties which can be used as both pre-and post-exposure treatments has significant advantages for protection against CWNA toxicity during war or terrorist attacks.…”