Seizure-related opening of the blood-brain barrier produced by the anticholinesterase compound, soman: New ultrastructural observations

Previous macroscopic and light microscopic observations established that th e organophosphate soman, an irreversible inhibitor of cholinesterases, prod uces seizure-related opening of the blood-brain barrier (BBB) to proteins. In Wistar rats, this BBB alteration was found to be reversible. This altera tion was greatest during the first hour of seizures, and was topographicall y limited to sensitive areas such as the thalamus. In contrast, the hippoca mpus remained free of any vascular leakage. The present study is an attempt to elucidate, in rat thalamus, the subcellular mechanisms involved in soma n-induced BBB alteration. A combination of three ultrastructural approaches was used: examination of ultra-thin sections, freeze-fracture, and post-em bedding protein A-gold immunocytochemistry of the endogenous, normally excl usively blood-borne, albumin. Our findings show that soman-induced seizure activity produced no discernible structural change in the endothelial tight junctions, whereas it unambiguously increased the number of endothelial ve sicles. Finally, immunolabelled albumin clearly crossed the endothelium, bu t was not systematically found inside the endothelial vesicles. Altogether, the present ultrastructural study confirms that soman can alter the integr ity of the BBB, and demonstrates that the blood-to-brain passage of protein s does not mainly derive from the opening of tight junctions. Although tran scytosis is clearly increased through the cerebral endothelium, there is li ttle evidence that blood-borne proteins penetrate the brain in this way. Th e actual mechanisms of transport thus remain to be clarified.