Structure-efficiency relationships of cyclodextrin scavengers in the hydrolytic degradation of organophosphorus compounds.

New derivatives of cyclodextrins were prepared in order to determine the relative importance of the structural key elements involved in the degradation of organophosphorus nerve agents. To avoid a competitive inclusion between the organophosphorus substrate and the iodosobenzoate group, responsible for its degradation, the latter group had to be covalently bound to the cyclodextrin scaffold. Although the presence of the α nucleophile iodosobenzoate was a determinant in the hydrolysis process, an imidazole group was added to get a synergistic effect towards the degradation of the agents.

Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis.

In the present study, the toxicity of yperite, SM, and its structural analogue mechlorethamine, HN2, was investigated in a human bronchial epithelial cell line 16HBE. Cell detachment was initiated by caspase-2 activation, down-regulation of Bcl-2 and loss of mitochondrial membrane potential. Only in detached cells, mustards induced apoptosis associated with increase in p53 expression, Bax activation, decrease in Bcl-2 expression, opening of the mitochondrial permeability transition pore, release of cytochrome c, caspase-2, -3, -8, -9 and -13 activation and DNA fragmentation.

Effects of acetylcholinesterase and butyrylcholinesterase inhibition on breathing in mice adapted or not to reduced acetylcholinesterase.

We investigated the contributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition to the respiratory dysfunction produced by organophosphates in mice which were adapted or not to low AChE activity. Effects of acute selective inhibition of AChE and BChE on ventilation measured by whole-body plethysmography were compared in mice with either normal AChE activity (wild-type), or mice adapted to a null AChE activity (homozygotes for AChE gene deletion) or adapted to an intermediate level of activity (heterozygotes). In wild-type mice acute reduction of AChE by Huperzine A (1 mg/kg) to the level found in asymptomatic heterozygotes, induced tremors but no respiratory depression, whereas the same dose of Huperzine in heterozygote animals further reduced AChE activity, increased tidal volume (V(T)) and decreased breathing frequency (f(R)).

Respiratory survival mechanisms in acetylcholinesterase knockout mouse.

Cholinergic neurotransmission ensures muscle contraction and plays a role in the regulation of respiratory pattern in the brainstem. Inactivation of acetylcholinesterase (AChE) by organophosphates produces respiratory failure but AChE knockout mice survive to adulthood. Respiratory adaptation mechanisms which ensure survival of these mice were examined in vivo by whole body plethysmography and in vitro in the neonatal isolated brainstem preparation.