TY - JOUR
T1 - Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy
AU - Hartz, Anika M.S.
AU - Rempe, Ralf G.
AU - Soldner, Emma L.B.
AU - Pekcec, Anton
AU - Schlichtiger, Juli
AU - Kryscio, Richard
AU - Bauer, Bjoern
N1 - Publisher Copyright:
© FASEB.
PY - 2019/12
Y1 - 2019/12
N2 - Blood-brain barrier dysfunction in epilepsy contributes to seizures and resistance to antiseizure drugs. Reports show that seizures increase brain glutamate levels, leading to barrier dysfunction. One component of barrier dysfunction is overexpression of the drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Based on our previous studies, we hypothesized that glutamate released during seizures activates cytosolic phospholipase A2 (cPLA2), resulting in P-gp and BCRP overexpression. We exposed isolated rat brain capillaries to glutamate ex vivo and used an in vivo-ex vivo approach of isolating brain capillaries from rats after status epilepticus (SE) and in chronic epileptic (CE) rats. Glutamate increased cPLA2, P-gp, and BCRP protein and activity levels in isolated brain capillaries. We confirmed the role of cPLA2 in the signaling pathway in brain capillaries from male and female mice lacking cPLA2. We also demonstrated, in vivo, that cPLA2 inhibition prevents overexpression of P-gp and BCRP at the blood-brain barrier in rats after status epilepticus and in CE rats. Our data support the hypothesis that glutamate signals cPLA2 activation, resulting in overexpression of blood-brain barrier P-gp and BCRP.—Hartz, A. M. S., Rempe, R. G., Soldner, E. L. B., Pekcec, A., Schlichtiger, J., Kryscio, R., Bauer, B. Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy. FASEB J. 33, 14281-14295 (2019). www.fasebj.org.
AB - Blood-brain barrier dysfunction in epilepsy contributes to seizures and resistance to antiseizure drugs. Reports show that seizures increase brain glutamate levels, leading to barrier dysfunction. One component of barrier dysfunction is overexpression of the drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Based on our previous studies, we hypothesized that glutamate released during seizures activates cytosolic phospholipase A2 (cPLA2), resulting in P-gp and BCRP overexpression. We exposed isolated rat brain capillaries to glutamate ex vivo and used an in vivo-ex vivo approach of isolating brain capillaries from rats after status epilepticus (SE) and in chronic epileptic (CE) rats. Glutamate increased cPLA2, P-gp, and BCRP protein and activity levels in isolated brain capillaries. We confirmed the role of cPLA2 in the signaling pathway in brain capillaries from male and female mice lacking cPLA2. We also demonstrated, in vivo, that cPLA2 inhibition prevents overexpression of P-gp and BCRP at the blood-brain barrier in rats after status epilepticus and in CE rats. Our data support the hypothesis that glutamate signals cPLA2 activation, resulting in overexpression of blood-brain barrier P-gp and BCRP.—Hartz, A. M. S., Rempe, R. G., Soldner, E. L. B., Pekcec, A., Schlichtiger, J., Kryscio, R., Bauer, B. Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy. FASEB J. 33, 14281-14295 (2019). www.fasebj.org.
KW - BCRP
KW - P-glycoprotein
KW - neurovascular unit
KW - seizures
UR - http://www.scopus.com/inward/record.url?scp=85076123465&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076123465&partnerID=8YFLogxK
U2 - 10.1096/fj.201901369RR
DO - 10.1096/fj.201901369RR
M3 - Article
C2 - 31661303
AN - SCOPUS:85076123465
SN - 0892-6638
VL - 33
SP - 14281
EP - 14295
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -
