To probe encephalopathy pathogenesis during toxic shock syndrome (TSS), we investigated the fate of bloodborne TSS toxin-1 (TSST-1) as it moves through the choroid plexus epithelium that forms the main blood-cerebrospinal fluid (CSF) barrier and the effect that TSST-1 has on choroidal barrier properties and on cultured neuronal cell viability. TSST-1 showed a slow, diffusional movement across a cellular model of the blood-CSF barrier but did not compromise the integrity of the barrier. Relevant to the acute symptoms of TSS, a combination of human leukocytes and the toxin induced a decrease in CSF clearance of the pyrogenic prostaglandin E(2) (PGE(2)). The direct effects that TSST-1 had on primary cortical neuron cultures and a neuronal cell line involved elevated caspase 3/7 levels, which correlated with an increase in neuronal cell death. The results of the present study suggest that TSST-1 can affect the brain, by inducing both an intracerebral increase in PGE(2) concentration and caspase-dependent neuronal death, which are possibly relevant to long-term intoxication.