TY  - JOUR
A1  - Janssen, Lisa
A1  - Ai, Xiaoyu
A1  - Zheng, Xuan
A1  - Wei, Wei
A1  - Caglayan, Ahmet B.
A1  - Kilic, Ertugrul
A1  - Wang, Ya-chao
A1  - Hermann, Dirk Matthias
A1  - Venkataramani, Vivek
A1  - Bähr, Mathias
A1  - Döppner, Thorsten Roland
T1  - Inhibition of fatty acid synthesis aggravates brain injury, reduces blood-brain barrier integrity and impairs neurological recovery in a murine stroke model
T2  - Frontiers in cellular neuroscience
N2  - Inhibition of fatty acid synthesis (FAS) stimulates tumor cell death and reduces angiogenesis. When SH-SY5Y cells or primary neurons are exposed to hypoxia only, inhibition of FAS yields significantly enhanced cell injury. The pathophysiology of stroke, however, is not only restricted to hypoxia but also includes reoxygenation injury. Hence, an oxygen-glucose-deprivation (OGD) model with subsequent reoxygenation in both SH-SY5Y cells and primary neurons as well as a murine stroke model were used herein in order to study the role of FAS inhibition and its underlying mechanisms. SH-SY5Y cells and cortical neurons exposed to 10 h of OGD and 24 h of reoxygenation displayed prominent cell death when treated with the Acetyl-CoA carboxylase inhibitor TOFA or the fatty acid synthase inhibitor cerulenin. Such FAS inhibition reduced the reduction potential of these cells, as indicated by increased NADH2+/NAD+ ratios under both in vitro and in vivo stroke conditions. As observed in the OGD model, FAS inhibition also resulted in increased cell death in the stroke model. Stroke mice treated with cerulenin did not only display increased brain injury but also showed reduced neurological recovery during the observation period of 4 weeks. Interestingly, cerulenin treatment enhanced endothelial cell leakage, reduced transcellular electrical resistance (TER) of the endothelium and contributed to poststroke blood-brain barrier (BBB) breakdown. The latter was a consequence of the activated NF-κB pathway, stimulating MMP-9 and ABCB1 transporter activity on the luminal side of the endothelium. In conclusion, FAS inhibition aggravated poststroke brain injury as consequence of BBB breakdown and NF-κB-dependent inflammation.
KW  - blood-brain barrier
KW  - cerebral ischemia
KW  - fatty acid synthesis
KW  - hypoxia
KW  - neuroprotection
KW  - reduction potential
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62031
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-620314
SN  - 1662-5102
VL  - 15
IS  - art. 733973
SP  - 1
EP  - 15
PB  - Frontiers Research Foundation
CY  - Lausanne
ER  -