Comparative effects of scopolamine and phencynonate on organophosphorus nerve agent-induced seizure activity, neuropathology and lethality

Abstract

The efficacy of anticonvulsant therapies to stop seizure activities following organophosphorus nerve agents (NAs) has been documented as being time-dependent. We utilized the guinea pig NA-seizure model to compare the effectiveness of phencynonate (PCH) and scopolamine (SCP) when given at the early (at time of seizure onset) or late (40 min after seizure onset) phase of seizure progression. PCH possesses both anticholinergic and anti-NMDA activities, while SCP is a purely anti-muscarinic compound. Animals with cortical electrodes were pretreated with pyridostigmine bromide 30 min prior to exposure to a 2.0 x LD₅₀ subcutaneous dose of a NA (GA, GB, GD, GF, VR, or VX), followed one min later with atropine sulfate and 2-PAM. At either early or late phase, animals were treated with either PCH or SCP and the 24-h anticonvulsant ED₅₀ doses were determined. When administered at seizure onset, PCH, and SCP were both effective at terminating seizure activity against all NAs, with ED₅₀ values for SCP generally being lower. At the 40 min time, ED₅₀ values were obtained following GA, GD, GF, and VR challenges for SCP, but ED₅₀ value was obtained only following GD for PCH, indicating a superior efficacy of SCP. When seizure activity was controlled, a significant improvement in weight loss, neuropathology, and survival was observed, regardless of treatment or NA. Overall, these results demonstrate the differing efficacies of these two similarly structured anticholinergic compounds with delayed administration and warrant further investigation into the timing and mechanisms of the seizure maintenance phase in different animal models.

Keywords:

• Phencynonate
• scopolamine
• seizure activity
• neuropathology
• lethality
• nerve agents
• organophosphorus compounds
• sarin
• soman
• cyclosarin
• tabun
• VR
• VX

Acknowledgments

This research was supported in part by an appointment (Jeffrey A. Koenig and Cindy Acon Chen) to the Postgraduate Research Participation Program at the U.S. Army Medical Research Institute of Chemical Defense administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and USAMRMC. The excellent technical team work of Jessica Chandler and Amy Wegener is acknowledged.

Disclosure statement

No potential conflict of interest was reported by the authors.

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the United States Government. The experimental protocol was approved by the Institutional Animal Care and Use Committee at the United States Army Medical Research Institute of Chemical Defense and all procedures were conducted in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act of 1966 (P.L. 89-544), as amended. The facility where this research was conducted is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International.

Additional information

Funding

This project was funded by the Defense Threat Reduction Agency – Joint Service and Technology Office, Medical Science and Technology Division.