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Blood–brain barrier (BBB) is specialized to limit brain drug delivery. Cross-reacting material 197 (CRM197), a non-toxic mutant of diphtheria toxin, could act as a diphtheria toxin receptor-specific carrier protein and deliver drugs across the BBB. CRM197 has previously been shown to inhibit phospatidyl-3-inositol-kinase (PI3K)/Akt signaling. Other studies have demonstrated a link between PI3K/Akt signaling and forkhead transcription factors in endothelial cells. We therefore investigated the effects and mechanisms underlying the potential of CRM197, not only as a carrier protein for targeted drug delivery to the brain, but also for inducing signaling to affect endocytosis in endothelial cells. The hCMEC/D3 cell line had been used to establish a BBB in vitro model; the transport efficiency of CRM197 was analyzed both by association and transcytosis experiments. CRM197 was shown to prefer apical-to-basal transcytosis, which involved the caveolae-mediated pathway. The uptake of CRM197 conjugates by endothelial cells reached equilibrium after 60 min of treatment. The caveolin-1 mRNA and protein expression levels were significantly increased by CRM197. The up-regulation of caveolin-1 may be mediated by CRM197 via a PI3K/Akt dependent pathway and reduction of the phospho-FOXO1A (forkhead box O) transcription factor. Our results indicate that carrier protein CRM197-mediated delivery across the BBB is involved in the induction of FOXO1A transcriptional activity and upregulation of caveolin-1 expression. [ABSTRACT FROM AUTHOR]

The article presents the correction for a article titled "Lower glomerular filtration rate after mild stroke induces cognitive impairment by causing endothelial dysfunction" published online on August 26, 2024.