In vitro and in vivo Evaluation of the Efficacy of Recombinant Human Liver Prolidase as a Catalytic Bioscavenger of Chemical Warfare Nerve Agents.

摘要

Chemical warfare nerve agents (NAs) are among the deadliest compounds known to man, and they pose a great threat to military personnel and civilians alike. Their toxicity stems from their ability to inhibit acetylcholinesterase (AChE), which is responsible for the breakdown of the neurotransmitter acetylcholine (ACh) (De Candole et al., 1953; Yokoyama et al., 1998). The resultant accumulation of ACh at cholinergic synapses produces an acute cholinergic crisis characterized by miosis, increased tracheobronchial and salivary secretions, bronchoconstriction, bradycardia, fasciculations, behavioral incapacitation, muscular weakness, and convulsions culminating in death by respiratory failure (Brimblecombe, 1977). Developing a viable treatment for these toxicities has been a scientific challenge, and different therapeutic approaches are being investigated. Currently, treatment of NA intoxication involves the use of a combination of pharmacological therapies to counteract the effects of NA-induced inhibition of AChE. This treatment includes cholinolytic drugs such as atropine sulfate, a competitive antagonist of the acetylcholine receptors (Shih & McDonough, 1999; Shih et al., 2007), oximes such as pyridinium-2-aldoxime (2-PAM) to restore the activity of NA-inhibited AChE, (Gray, 1984; Haigh et al., 2005; Koplovitz & Stewart, 1994) and anticonvulsant drugs such as diazepam to control NA-induced tremors and seizures (Dickson et al., 2003; Marti et al., 1985; Shih et al., 2007). Although these treatments effectively prevent NA lethality, they do not prevent performance deficits, loss of consciousness, or permanent brain damage (Dirnhuber et al., 1979).