Blood-Brain Barrier Rescue by Roflumilast After Transient Global Cerebral Ischemia in Rats

J.M. Bonato; B.A. de Mattos; D.V. Oliveira; H. Milani; J. Prickaerts; R.M.W. de Oliveira

doi:10.1007/s12640-023-00639-2

Blood-Brain Barrier Rescue by Roflumilast After Transient Global Cerebral Ischemia in Rats

J.M. Bonato, B.A. de Mattos, D.V. Oliveira, H. Milani, J. Prickaerts, R.M.W. de Oliveira^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	311-323
Number of pages	13
Journal	Neurotoxicity Research
Volume	41
Issue number	4
Early online date	1 Mar 2023
DOIs	https://doi.org/10.1007/s12640-023-00639-2
Publication status	Published - Aug 2023

Keywords

Phosphodiesterase inhibitor
Roflumilast
Transient global cerebral ischemia
The blood-brain barrier
NITRIC-OXIDE SYNTHASE
PHOSPHODIESTERASE-4 INHIBITOR
ROLIPRAM PROTECTS
ARTERY OCCLUSION
NEURONAL DEATH
CARDIAC-ARREST
STROKE
HIPPOCAMPUS
DAMAGE
INFLAMMATION

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Cite this

@article{e76d23d648b44dc3bf97188c2b63c57f,

title = "Blood-Brain Barrier Rescue by Roflumilast After Transient Global Cerebral Ischemia in Rats",

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.",

keywords = "Phosphodiesterase inhibitor, Roflumilast, Transient global cerebral ischemia, The blood-brain barrier, NITRIC-OXIDE SYNTHASE, PHOSPHODIESTERASE-4 INHIBITOR, ROLIPRAM PROTECTS, ARTERY OCCLUSION, NEURONAL DEATH, CARDIAC-ARREST, STROKE, HIPPOCAMPUS, DAMAGE, INFLAMMATION",

author = "J.M. Bonato and {de Mattos}, B.A. and D.V. Oliveira and H. Milani and J. Prickaerts and {de Oliveira}, R.M.W.",

note = "Funding Information: This study was funded by CAPES/NUFFIC Program (number 88881.156529/2017–0. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2023",

month = aug,

doi = "10.1007/s12640-023-00639-2",

language = "English",

volume = "41",

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journal = "Neurotoxicity Research",

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T1 - Blood-Brain Barrier Rescue by Roflumilast After Transient Global Cerebral Ischemia in Rats

AU - Bonato, J.M.

AU - de Mattos, B.A.

AU - Oliveira, D.V.

AU - Milani, H.

AU - Prickaerts, J.

AU - de Oliveira, R.M.W.

N1 - Funding Information: This study was funded by CAPES/NUFFIC Program (number 88881.156529/2017–0. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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.

KW - Phosphodiesterase inhibitor

KW - Roflumilast

KW - Transient global cerebral ischemia

KW - The blood-brain barrier

KW - NITRIC-OXIDE SYNTHASE

KW - PHOSPHODIESTERASE-4 INHIBITOR

KW - ROLIPRAM PROTECTS

KW - ARTERY OCCLUSION

KW - NEURONAL DEATH

KW - CARDIAC-ARREST

KW - STROKE

KW - HIPPOCAMPUS

KW - DAMAGE

KW - INFLAMMATION

U2 - 10.1007/s12640-023-00639-2

DO - 10.1007/s12640-023-00639-2

M3 - Article

C2 - 36922461

SN - 1029-8428

VL - 41

SP - 311

EP - 323

JO - Neurotoxicity Research

JF - Neurotoxicity Research

IS - 4

ER -