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

Abstract

Galantamine, a drug currently approved for treatment of Alzheimer's disease, has recently emerged as an effective pretreatment against the acute toxicity and delayed cognitive deficits induced by organophosphorus (OP) nerve agents, including soman. Since cognitive deficits can result from impaired glutamatergic transmission in the hippocampus, the present study was designed to test the hypothesis that hippocampal glutamatergic transmission declines following an acute exposure to soman and that this effect can be prevented by galantamine. To test this hypothesis, spontaneous excitatory postsynaptic currents (EPSCs) were recorded from CA1 pyramidal neurons in hippocampal slices obtained at 1 h, 24 h, or 6-9 days after guinea pigs were injected with: (i) 1xLD50 soman (26.3 μg/kg, s.c.); (ii) galantamine (8 mg/kg, i.m.) followed 30 min later by 1xLD50 soman, (iii) galantamine (8 mg/kg, i.m.), or (iv) saline (0.5 ml/kg, i.m.). In soman-injected guinea pigs that were not pretreated with galantamine, the frequency of EPSCs was significantly lower than that recorded from saline-injected animals. There was no correlation between the severity of soman-induced acute toxicity and the magnitude of soman-induced reduction of EPSC frequency. Pretreatment with galantamine prevented the reduction of EPSC frequency observed at 6-9 days after the soman challenge. Prevention of soman-induced long-lasting reduction of hippocampal glutamatergic synaptic transmission may be an important determinant of the ability of galantamine to counter cognitive deficits that develop long after an acute exposure to the nerve agent.

Nerve Agents: What They Are, How They Work, How to Counter Them

“…Beyond the ATNAA, the United States Food and Drug Administration (FDA) approved the reversible acetylcholinesterase inhibitor pyridostigmine for the pretreatment of military personnel at risk of nerve agent exposure (Figure , pyridostigmine). , Although the use of an acetylcholinesterase inhibitor to prevent poisoning from nerve agents may seem counterintuitive, pretreatment with pyridostigmine makes the enzyme’s catalytic site less available to nerve agents, thus protecting from their toxicity. However, pyridostigmine too is not permeable to the blood–brain barrier; thus, its action is confined to outside the CNS …”

Donepezil increases resistance to induced seizures in a mouse model of Dravet syndrome

“…There is evidence to suggest that reversible AChE inhibitors might also be beneficial in the treatment of epilepsy. Donepezil, galantamine, and Huperzine A (Hup A), a naturally occurring reversible AChE inhibitor, have been shown to protect against soman‐induced seizures . Hup A also provides protection against N‐methyl‐D‐aspartate (NMDA)‐induced status epilepticus (SE) and pentylenetetrazole (PTZ)‐induced seizures in rats and zebrafish .…”

Long‐term neuropathological and behavioral impairments after exposure to nerve agents

“…41 In this pathophysiological environment, synaptic plasticity in the BLA is also impaired, albeit transiently. 14,24 In the hippocampus, decreased frequency of spontaneous excitatory postsynaptic currents (EPSCs) recorded from CA1 pyramidal neurons has been observed at 6-9 days after soman exposure, 43 which probably implies reduction in the glutamatergic inputs to these neurons because of neuronal degeneration and loss in the CA1 and CA3 hippocampal subfields. [11][12][13]15 During this time (6-9 days after exposure), the frequency of spontaneous IPSCs in CA1 pyramidal neurons has returned to control levels, after a transient reduction observed at 24 h after exposure, while their amplitude is larger than that in control rats.…”