Abstract
Phosphodiesterase 4 inhibitors (PDE4-I), which selectively increase cyclic adenosine monophosphate (cAMP) levels, have shown neuroprotective effects after several neurological injuries inducing blood–brain barrier (BBB) damage including local/focal cerebral ischemia. The present investigated whether roflumilast confers BBB neuroprotection in the hippocampus after transient global cerebral ischemia (TGCI) in rats. TGCI resulted in whole BBB disruption as measured by the increase of Evans blue (EB) and IgG extravasation, neurodegeneration, and downregulation of claudin-5 and endothelial nitric oxide synthase (eNOS) levels in the CA1 hippocampal subfield of ischemic rats. Roflumilast attenuated BBB disruption and restored the levels of eNOS in the CA1 hippocampal area. Moreover, roflumilast increased the levels of B2 cell lymphoma (BcL-2) and neuron-glial antigen-2 (NG2) in the CA1 subfield after global ischemia in rats. The protective effects of roflumilast against TGCI-induced BBB breakdown might involve preservation of BBB integrity, vascularization and angiogenesis, and myelin repair.
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This study was funded by CAPES/NUFFIC Program (number 88881.156529/2017–0.
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JM Bonato conducted the animals’ surgeries and biochemical assays. She wrote the first draft of the manuscript. BA de Mattos and DV Oliveira helped to perform the animals’ surgeries. H Milani analyzed the data and helped with statistical analysis. J Prickaerts and RMW Oliveira conceived the experimental design, planned the experiments, and performed the data workup. They also contributed to writing the manuscript. All authors discussed the results and commented on the manuscript.
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Highlights
• Transient global cerebral ischemia (TGCI) results in blood-brain barrier (BBB) disruption, neurodegeneration, and a decrease in claudin-5 and eNOS levels in the CA1 hippocampal subfield of rats.
• Roflumilast attenuates BBB disruption and increases the claudin-5 levels in the CA1 hippocampal area of TGCI rats.
• Roflumilast prevents eNOS decreases after TGCI and increases the levels of BcL-2 in the CA1 hippocampus of ischemic rats.
• Roflumilast increases the NG2-glia levels in the CA1 hippocampal area after TGCI in rats.
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Bonato, J.M., de Mattos, B.A., Oliveira, D.V. et al. Blood–Brain Barrier Rescue by Roflumilast After Transient Global Cerebral Ischemia in Rats. Neurotox Res 41, 311–323 (2023). https://doi.org/10.1007/s12640-023-00639-2
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DOI: https://doi.org/10.1007/s12640-023-00639-2