Low-dose cholinesterase inhibitors do not induce delayed effects on cerebral blood flow and metabolism

Abstract

The acetylcholinesterase (AChE) inhibitors sarin and pyridostigmine bromide (PB) have been proposed as causes of neurobehavioral dysfunction in Persian Gulf War veterans. To test possible delayed effects of these agents, we exposed rats to low (subsymptomatic) levels of sarin (0.5 LD 50 s.c. 3 times weekly) and/or PB (80 mg/L in drinking water) for 3 weeks. Controls received saline s.c. and tap water. At 2, 4 and 16 weeks after exposure, regional cerebral blood flow (rCBF) and glucose utilization (rCGU) were measured in conscious animals with the Iodo- 14C-antipyrine and 14C-2 deoxyglucose methods, respectively. Two weeks after exposure, PB+sarin caused significant rCBF elevations, but no changes in rCGU, in neocortex, with lesser effects on allocortex. Four weeks after exposure, the same general pattern was found with sarin. Only a few changes were found at 16 weeks post-treatment. The predominant effects of sarin or PB+sarin on rCBF at earlier times after treatment are consistent with the well known direct cerebral vascular effect of cholinergic agonists. The lack of changes in rCBF and rCGU observed at 16 weeks after treatment does not support the hypothesis that repeat exposure to low-dose cholinesterase inhibitors can generate permanent alterations in cerebral activity.