TY - JOUR
T1 - Overexpression of Mfsd2a attenuates blood brain barrier dysfunction via Cav-1/Keap-1/Nrf-2/HO-1 pathway in a rat model of surgical brain injury
AU - Eser Ocak, Pinar
AU - Ocak, Umut
AU - Sherchan, Prativa
AU - Gamdzyk, Marcin
AU - Tang, Jiping
AU - Zhang, John H.
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/4
Y1 - 2020/4
N2 - Introduction: Disruption of the blood brain barrier (BBB) and subsequent cerebral edema formation is one of the major adverse effects of brain surgery, leading to postoperative neurological dysfunction. Recently, Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions. In this study, we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury (SBI) in rats. Materials and methods: Rats were subjected to SBI by partial resection of the right frontal lobe. To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI, Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids, respectively. The potential mechanism of Mfsd2a-mediated BBB protection through the cav-1/Nrf-2/HO-1 signaling pathway was evaluated. Results: Mfsd2a levels were significantly decreased while cav-1, Nrf-2 and HO-1 levels were increased in the right frontal perisurgical area following SBI. When overexpressed, Mfsd2a attenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI. The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav-1, increased Keap-1/Nrf-2 dissociation and further augmented levels of Nrf-2 and HO-1 in the right frontal perisurgical area, leading to enhanced levels of tight junction proteins following SBI. The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf-2 and HO-1. Conclusions: Mfsd2a attenuates BBB disruption through cav-1/Nrf-2/HO-1 signaling pathway in rats subjected to experimental SBI.
AB - Introduction: Disruption of the blood brain barrier (BBB) and subsequent cerebral edema formation is one of the major adverse effects of brain surgery, leading to postoperative neurological dysfunction. Recently, Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions. In this study, we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury (SBI) in rats. Materials and methods: Rats were subjected to SBI by partial resection of the right frontal lobe. To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI, Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids, respectively. The potential mechanism of Mfsd2a-mediated BBB protection through the cav-1/Nrf-2/HO-1 signaling pathway was evaluated. Results: Mfsd2a levels were significantly decreased while cav-1, Nrf-2 and HO-1 levels were increased in the right frontal perisurgical area following SBI. When overexpressed, Mfsd2a attenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI. The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav-1, increased Keap-1/Nrf-2 dissociation and further augmented levels of Nrf-2 and HO-1 in the right frontal perisurgical area, leading to enhanced levels of tight junction proteins following SBI. The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf-2 and HO-1. Conclusions: Mfsd2a attenuates BBB disruption through cav-1/Nrf-2/HO-1 signaling pathway in rats subjected to experimental SBI.
KW - Blood brain barrier
KW - Brain edema
KW - Cav-1
KW - Caveolae
KW - Mfsd2a
KW - Surgical brain injury
KW - Genetic Therapy
KW - Signal Transduction/genetics
KW - Rats
KW - Male
KW - Treatment Outcome
KW - Blood-Brain Barrier/physiopathology
KW - Rats, Sprague-Dawley
KW - Behavior, Animal
KW - Kelch-Like ECH-Associated Protein 1/genetics
KW - Brain Injuries/genetics
KW - Heme Oxygenase (Decyclizing)/genetics
KW - Animals
KW - Body Water/metabolism
KW - Caveolin 1/genetics
KW - Frontal Lobe/injuries
KW - NF-E2-Related Factor 2/genetics
UR - http://www.scopus.com/inward/record.url?scp=85078106610&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078106610&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/e1c8ef2d-a047-35bb-bacb-9c62f08d9241/
U2 - 10.1016/j.expneurol.2020.113203
DO - 10.1016/j.expneurol.2020.113203
M3 - Article
C2 - 31954682
SN - 0014-4886
VL - 326
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 113203
ER -