Viral neuroinvasion as a marker for BBB integrity following exposure to cholinesterase inhibitors

Exposure to the nerve agent soman, an irreversible cholinesterase (ChE) inh ibitor, results in changes in blood-brain barrier permeability attributed t o its seizure-induced activity. However, smaller BBB changes may be indepen dent of convulsions. Such minor injury may escape detection. A nonneuroinva sive neurovirulent Sindbis virus strain (SVN) was used as a marker for BBB permeability. Peripheral inoculation of mice with 2X10(3) plaque forming un its (PFU) caused up to 10(5) PFU/ml viremia after 24 hours with no signs of central nervous system (CNS) infection and with no virus detected in brain tissue. Intra-cerebral injection of as low as 1-5 PFU of the same virus ca used CNS infection, exhibited 5-7 days later as hind limb paralysis and dea th. Soman (0.1-0.7 of the LD50,) was administered at peak viremia (1 day fo llowing peripheral inoculation). Sublethal soman exposure at as low as 0.1L D(50) resulted in CNS infection 6-8 days following inoculation in 30-40% of the mice. High virus titer were recorded in brain tissue of sick mice whil e no virus was detected in healthy mice subjected to the same treatment. No changes in the level of viremia or changes in viral traits were observed i n the infected mice. The reversible anticholinesterases physostigmine (0.2 mg/kg, s.c.) and pyridostigmine (OA mg/kg, i.m.) injected at a dose equal t o 0.1LD(50) induced similar results. Thus, both central and peripheral anti cholinesterases (anti-ChEs) induce changes in BBB permeability sufficient t o allow, at least in some of the mice, the invasion of this otherwise nonin vasive but highly neurovirulent virus. This BBB change is probably due to t he presence of cholinesterases in the capillary wall. SVN brain invasion se rved here as a highly sensitive and reliable marker for BBB integrity. (C) 2001 Elsevier Science Inc. All rights reserved.