Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy

Article

关键词: CANCER RESISTANCE PROTEIN;    GLYCOPROTEIN-MEDIATED TRANSPORT;    INDUCED UP-REGULATION;    MAJOR VAULT PROTEIN;    P-GLYCOPROTEIN;    MULTIDRUG-RESISTANCE;    ANTIEPILEPTIC DRUGS;    CENTELLA-ASIATICA;    ABC TRANSPORTERS;    CYCLOOXYGENASE 2;   

DOI  :  10.1096/fj.201901369RR

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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